Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia

Study Overview
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Brief Summary
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This phase II trial studies how well total-body irradiation (TBI) works when given together with fludarabine phosphate and cyclophosphamide followed by donor bone marrow transplant, mycophenolate mofetil, and cyclosporine in treating patients with Fanconi anemia (FA). Giving low doses of chemotherapy, such as fludarabine phosphate and cyclophosphamide, and TBI before or after a donor bone marrow transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine after the transplant may stop this from happening.

Detailed Description
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PRIMARY OBJECTIVES: I. Identify doses of total-body irradiation (TBI) that lead to sufficient probability of donor engraftment (> 5% donor cluster of differentiation [CD]3 chimerism) by day +200. II. Evaluate the probability of severe acute graft-versus-host disease. SECONDARY OBJECTIVES: I. Evaluate the probabilities of overall survival, regimen-related toxicity (RRT), and recurrent hematopoietic malignancy in those patients with a prior underlying history of such. II. Examine the degree to which mixed chimerism provides for amelioration of symptoms (i.e., infections due to neutropenia, hemorrhage due to thrombocytopenia) associated with bone marrow failure. III. Determine if the FA complementation group and % initial mosaicism predict engraftment and RRT outcomes. OUTLINE: Patients are assigned to 1 of 4 treatment arms. NOTE: Patients no longer receive pre-transplant cyclophosphamide as of February 2009. After completion of study treatment, patients are followed up at 6 months and then annually thereafter.

Official Title
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Nonmyeloablative Hematopoietic Cell Transplantation for Patients With Fanconi Anemia Using Alternative Marrow Donors: A Phase II Dose-Finding Study

Conditions
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Acute Myeloid Leukemia in Remission, de Novo Myelodysplastic Syndrome, Fanconi Anemia, Previously Treated Myelodysplastic Syndrome

Intervention / Treatment
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* Procedure: Allogeneic Bone Marrow Transplantation
* Drug: Cyclophosphamide
* Drug: Cyclosporine
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Mycophenolate Mofetil
* Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
* Radiation: Total-Body Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient with FA and bone marrow (BM) failure involving 2 of the following 3 lineages: granulocyte count < 0.5 x 10^9/L, platelet count < 20 x 10^9/L, or hemoglobin < 8 g/dL Any patient with FA who requires red blood cell or platelet transfusions because of marrow failure Any patient with FA who has a life-threatening BM failure involving a single hematopoietic lineage Any patient with FA and pre-existing cytogenetic abnormality including hematopoietic malignancy (acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) in morphological remission (defined as absence of circulating blasts and bone marrow blasts < 5% as assessed by morphology); Note that hematopoietic recovery is not required for remission status Patients must have a negative cytotoxic cross match with donor DONOR: Related, human leukocyte antigen (HLA)-haploidentical donors must be identical for one HLA haplotype and mismatched for any number of HLA-A, -B, -C, DRB1 or DQB1 loci of the unshared haplotype DONOR: Unrelated, HLA-matched donors must be matched at HLA-A, B, C, DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing at the highest resolution routinely available at the time of donor selection; a single allele mismatch at HLA-A, B, or C is allowed OR a single DQB1 mismatch is allowed DONOR: Bone marrow will be the only allowed hematopoietic stem cell source DONOR: Haploidentical donor selection will be based on standard institutional criteria, otherwise no specific prioritization will be made amongst the suitable available donors Exclusion Criteria: Patients having available HLA-matched related donors Significant organ dysfunction that would prevent compliance with conditioning, graft-versus-host disease (GVHD) prophylaxis, or would severely limit the probability of survival, such as liver disease/failure (active hepatitis, moderate to severe portal fibrosis/cirrhosis confirmed by biopsy or uncorrectable hepatic synthetic dysfunction), lung disease, or cardiac disease (ejection fraction < 35%, or if unable to obtain ejection fraction, shortening fraction of < 26%; if shortening is < 26% a cardiology consult is required with principal investigator [PI] having final approval of eligibility) Human immunodeficiency virus (HIV) seropositive patients Fertile females who are unwilling to use contraceptive techniques during and for the twelve months following treatment, as well as females who are pregnant or actively breast feeding Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment AML/MDS in morphological relapse, defined as having circulating blasts or bone marrow blasts >= 5% as assessed by morphology Active infectious disease concerns Karnofsky performance score < 50 or Lansky performance score < 40 DONOR: Donors found to have Fanconi anemia based on chromosomal breakage analysis DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1 x 10^8 nucleated cells/kg recipient ideal body weight [IBW]) or who are unwilling to be bone marrow donors DONOR: HIV-positive donors DONOR: Donors who are cross-match positive with recipient DONOR: Recipient homozygous at mismatched locus; if the recipient is homozygous at HLA-A, B, or C and the donor is mismatched at that locus, the donor should be avoided; exceptions must be discussed with the PI
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (2 vs 2.5 vs 3 Gy TBI dose-escalation)<br>Patients with a history of hematologic malignancy and HLA-haploidentical donor receive fludarabine phosphate (FLU) intravenously (IV) over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF orally (PO) thrice daily (TID) on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo allogeneic bone marrow transplant<br>* Other names: Allogeneic BMT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cyclosporine<br>* Given IV or PO<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic stem cell transplant<br>* Other names: NST;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;|
| Experimental: Arm II (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)<br>Patients with no history of hematological malignancy and HLA-haploidentical donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo allogeneic bone marrow transplant<br>* Other names: Allogeneic BMT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cyclosporine<br>* Given IV or PO<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic stem cell transplant<br>* Other names: NST;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;|
| Experimental: Arm III (2 vs 2.5 vs 3 Gy TBI dose-escalation)<br>Patients with history of hematologic malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo allogeneic bone marrow transplant<br>* Other names: Allogeneic BMT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cyclosporine<br>* Given IV or PO<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic stem cell transplant<br>* Other names: NST;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;|
| Experimental: Arm IV (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)<br>Patients with no history of hematological malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo allogeneic bone marrow transplant<br>* Other names: Allogeneic BMT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cyclosporine<br>* Given IV or PO<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic stem cell transplant<br>* Other names: NST;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Engraft at Each Dose of TBI Used | Number of subjects who engrafted. Engraftment defined as greater than 95% donor chimerism. | Up to Day 200 | 
| Incidence of Grades III-IV Acute GVHD | Number of subjects who developed maximum grade acute graft-vs-host disease aGVHD Stages Skin: - a maculopapular eruption involving < 25% BSA - a maculopapular eruption involving 25 - 50% BSA - generalized erythroderma - generalized erythroderma with bullous formation and often with desquamation Liver: - bilirubin 2.0 - 3.0 mg/100 mL - bilirubin 3 - 5.9 mg/100 mL - bilirubin 6 - 14.9 mg/100 mL - bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade III: Stage 2 - 4 gastrointestinal involvement and/or +2 to +4 liver involvement, with or without a rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death | Up to Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Transplant-related Mortality | Number of subjects who expired due to transplant-related mortality | Up to Day 200 | 
| Incidence of Adverse Events | Number of subjects who developed reportable AEs, assessed using adapted version of the Common Toxicity Criteria | Up to Day 100 |