Transplantation of Partially Mismatched Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia

Study Overview
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Brief Summary
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Our primary objective is to determine if it is feasible for SAA patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide with partially HLA-mismatched donors.

Detailed Description
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This research is being done to find out if bone marrow transplantation (BMT) followed by chemotherapy will help people with aplastic anemia who have failed other treatments. You have a severe, life threatening disease (severe aplastic anemia) in your bone marrow. Your disease has come back or not responded after receiving one or more immunosuppressive treatments. High dose chemotherapy followed by bone marrow transplantation (BMT) has been used to treat blood diseases like yours but complications from Graft vs. Host disease (GVHD) and graft failure have limited the survival for those people. A small study done at Johns Hopkins has shown that in subjects with other diseases (blood cancers) some immunosuppressive drugs given after the BMT have decreased how often subjects had complications of GVHD and engraftment failure. People with aplastic anemia who have refractory disease (not responding to standard treatment) may join.

Official Title
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A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched/Haploidentical Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes

Conditions
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Severe Aplastic Anemia, Bone Marrow Failure Syndromes

Intervention / Treatment
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* Procedure: Bone marrow transplant
* Drug: Thymoglobulin
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: TBI
* Drug: Mesna
* Drug: Tacrolimus
* Drug: Mycophenolic acid mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with relapsed or refractory SAA or very SAA defined: Bone marrow (< 25% cellular) Peripheral cytopenias (at least 2 of 3) ANC < 500 per ml Platelets < 20,000 per ml Absolute retic < 60,000 or corrected retic < 1% Very severe: as above, but ANC < 200 Disease may be designated as acquired or inherited if previous counts known (these other bone marrow failure disorders that are characterized by aplastic anemia may go by additional names such as dyskeratosis congenita or PNH) Failed at least one course of immunosuppressive therapy (if presumed acquired disease). Patients with inherited disease will be characterized as refractory and do not require immunosuppressive first. Age 0- upper age limit as determined by current institutional standards Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100) Patients and donors must be able to sign consent forms (or if a minor the parent will sign). Donors should be willing to donate. Patients must be geographically accessible and willing to participate in all stages of treatment. Adequate end-organ function as measured by: Left ventricular ejection fraction > or = to 35%, or shortening fraction > 25% (For pediatric patients, a normal ejection fraction is required) Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST ≤ 5 x ULN FEV1 and FVC > or = to 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation >92% on room air Exclusion Criteria: Patients will not be excluded on the basis of sex, racial or ethnic background. Prior transfusions from selected donor (as this could have cause recipient alloimmunization against the donor) Women of childbearing potential who currently are pregnant (HCG+) or who are not practicing adequate contraception. Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow up. Uncontrolled viral, bacterial, or fungal infections (HIV infection permitted if viral load undetectable)

Ages Eligible for Study
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Maximum Age: 73 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bone marrow transplant<br>Thymoglobulin on days -9 to -7 Fludarabine on days -6 to -2 Cyclophosphamide on days -6, -5, 3, 4 TBI on day -1 BMT on day 0 Mesna on days 3, 4 Tacrolimus on days 5-365 Mycophenolic acid mofetil on days 5-35 | Procedure: Bone marrow transplant<br>* Day 0<br>Drug: Thymoglobulin<br>* 0.5 mg/kg IV on Day -9 2 mg/kg IV on Days -8, -7<br>Drug: Fludarabine<br>* 30 mg/M2 IV on days -6 to -2<br>Drug: Cyclophosphamide<br>* 14.5 mg/kg IV on days -6, -5, 3, 4<br>* Other names: CTX;Radiation: TBI<br>* 200 cGy on day -1<br>Drug: Mesna<br>* 40 mg/kg IV on days 3, 4<br>Drug: Tacrolimus<br>* For patients 18 years or older, tacrolimus will be given per institutional standards; may be increased or later changed to a PO BID schedule. Treatment to continue until Day 365 or longer if GVHD present<br>Drug: Mycophenolic acid mofetil<br>* 15 mg/kg PO/IV TID beginning on day 5 through day 35<br>* Other names: MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Is This Type of Transplantation for Severe Aplastic Anemia Feasible and Safe? | Feasibility will be met with the following conditions: the patient has the transplant, is assessed for the safety endpoint, and survives one year. The safety monitoring plan is included to monitor graft failure (day 60), grade 2-4 acute graft versus host disease (day100), 6 month mortality (day 180), and chronic graft versus host disease (day 180). | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients That Have Survived at One Year |  | 1 year | 
| Number of Patients That Have Acheived Full Donor Chimerism by Day 60 After Transplant | Donor chimerism will be measured in the peripheral blood around day 30 and day 60. Patients with >5% donor chimerism around day 60 will be considered as having engrafted. | 60 days | 
| Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant |  | 1 year | 
| Number of Participants With Major Toxicities Related to Transplant |  | 1 year | 
| Number of Patients That Expired Due to Transplant Related Mortality |  | 1 year | 
| Number of Patients With Primary or Secondary Graft Failure Following Transplant | Graft failure: < 5% donor chimerism in blood and/or bone marrow on  Day 30 or after and on all subsequent measurements. Primary graft failure: < 5% donor chimerism in blood and/or bone marrow by   Day 56 Secondary graft failure: achievement of > 5% donor chimerism, followed by sustained <5% donor chimerism in blood and/or bone marrow. | 1 year | 
| Number of Participants With Grade II-IV or Grade III-IV Acute GVHD | Participants were graded during clinical visits based on evidence and extent of skin rash, liver involvement, and GI tract involvement | 1 year | 
| Participants With Chronic GVHD at One Year |  | 1 year | 
| Length of Time Required for Patients to Recover ANC and Platelet Counts After Transplant | CBC drawn daily with a WBC differential once the total WBC is greater than 100 until ANC > 500 for three days or two consecutive measurements over a three day period; then CBC drawn weekly with differential. | 1 year | 
| Participants That Were GVHD Free, Relapse Free Survival (GRFS) |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fludarabine, tacrolimus, Mycophenolic Acid Mofetil, bone marrow transplant, thymoglobulin, cyclophosphamide, chemotherapy, haploidentical, GVHD