Haploidentical Bone Marrow Transplant With Post-Transplant Cyclophosphamide for Patients With Severe Aplastic Anemia

Study Overview
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Brief Summary
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Severe aplastic anemia is a rare and serious form of bone marrow failure related to an immune-mediated mechanism that results in severe pancytopenia and high risk for infections and bleeding. Patients with matched sibling donors for transplantation have a 80-90% chance of survival; however, a response rate with just immunosuppression for those patients lacking suitable HLA-matched related siblings is only 60%. With immunosuppression, only 1/3 of patients are cured, 1/3 are dependent on long term immunosuppression, and the other 1/3 relapse or develop a clonal disorder. Recent studies have shown that using a haploidentical donor for transplantation has good response rates and significantly lower rates of acute and chronic GVHD.

Detailed Description
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Mismatched haploidentical donors will be identified for patients with severe aplastic anemia. These patients will undergo a preparative regimen of Fludarabine/Cyclophosphamide/TBI followed by haploidentical bone marrow transplantation. Post-transplant Cyclophosphamide will be administered on Days 3 & 4. Immunosuppression with Tacrolimus and MMF will begin on Day +5; MMF will be discontinued on Day +35 while Tacrolimus continues until Day +180. Investigators hypothesize that haploidentical transplantation with the above-mentioned preparative regimen will have a <30% graft failure rate. The one-sided exact Binomial test at 5% significance level will be used to test this hypothesis. The size of 20 patients provides the power of 92.5% for confirming the 30-day graft failure rate <30%.

Official Title
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A Study of T-Cell Replete, HLA-Mismatched Haploidentical Bone Marrow Transplantation With Post-Transplant Cyclophosphamide for Patients With Severe Aplastic Anemia Lacking HLA-Matched Related Donor

Conditions
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Severe Aplastic Anemia

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: Total Body Irradiation
* Drug: Rabbit ATG
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Availability of 3/6 - 5/6 matched (HLA-A, B, DR) related donor who must have negative HLA cross-match in the host vs. graft direction Age <= 65 years for previously treated and <= 75 years for previously treated patients KPS >= 70% Aplastic Anemia that meets the following criteria: Peripheral Blood (must fulfill 2 of 3): <500 PMN/mm3 <20,000 platelets absolute reticulocyte count <40,000/microL Bone Marrow (must be either): markedly hypocellular (<25% of normal cellularity) moderately hypocellular with 70% non-myeloid precursors and patient meets peripheral blood criteria above Exclusion Criteria: poor cardiac function (LVEF <40%) poor pulmonary function (FEV1 & FVC <50% predicted) poor liver function (bili >= 2mg/dL) poor renal function (creatinine >= 2.0mg/dL or creatinine clearance <40mL/min) prior allogeneic transplant

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 75 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: Flu/Cy/TBI<br>Fludarabine, Cyclophosphamide, TBI followed by bone marrow transplantation. Post-transplant Cyclophosphamide will be on Days 3 & 4. | Drug: Fludarabine<br>* 30 mg/m2 IV QD x 5 days (Days -6 to -2)<br>Drug: Cyclophosphamide<br>* 14.5 mg/kg/day IV x 2 doses (Days -6 & -5)<br>Radiation: Total Body Irradiation<br>* 300 cGy x1 dose (Day -1)<br>* Other names: TBI;Drug: Rabbit ATG<br>* 1.5 mg/kg/day x 3 days (Days -3 to -1)<br>Drug: Cyclophosphamide<br>* Post-transplant: 50 mg/kg IV QD (Day +3 to +4)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstrate sustained engraftment after T-cell replete HLA-mismatched haploidentical bone marrow transplantation by collecting chimerism tests monthly following transplant | Hypothesis is that following preparative regimen and bone marrow transplantation, the 30-day graft failure rate will be <30%. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the incidence of regimen-related mortality at 100 days post transplantation by recording treatment-related adverse events |  | 2 years | 
| Determine the incidence of grade 2-4 and 3-4 acute graft versus host disease at 100 days post transplantation by assessing signs and symptoms of GVHD throughout post-transplant course |  | 2 years | 
| Determine incidence of chronic GVHD at 6 months and 1 year post transplantation by assessing signs and symptoms of GVHD throughout post-transplant course |  | 2 years | 
| Estimate overall survival at 100 days and 1 year post transplantation by collecting survival information at those time points |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SAA