Haploidentical Transplant for People With Chronic Granulomatous Disease Using Post Transplant Cyclophosphamide

Study Overview
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Brief Summary
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Background: - Chronic Granulomatous Disease (CGD) causes immune system problems. Treatment is usually a bone marrow transplant from a fully matched donor. Researchers want to try using partially matched donors for patients who do not have a fully matched donor available. The researchers will also use the drug cyclophosphamide to try to improve the outcomes when using a partially matched donor. Objective: - To learn the effectiveness of using cyclophosphamide with a transplant from a partially matched donor in treating CGD. Eligibility: - Recipients: age 2-65 with CGD with an ongoing infection that has not been cured by standard treatment and no fully matched donor available in an appropriate timeframe. Design: Recipients will: be admitted to the hospital 2 weeks before transplant. be screened with blood and urine tests, breathing and heart health tests, X-rays, and/or magnetic resonance imaging. They may have a bone marrow aspiration and biopsy. meet with a social worker and dentist. get chemotherapy, radiation, and other medicines. get an intravenous (IV) catheter in their chest. have the transplant. get more medicines and standard supportive care. have blood drawn frequently. have to stay in the Washington, D.C. area for 3 months post-transplant. be followed closely for the first 6 months, and then less frequently for at least 5 years.

Detailed Description
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Allogeneic transplant using HLA matched donors, both related and unrelated, has proven curative for patients with various immunodeficiencies, including those with ongoing infections. However donor availability remains a limiting factor in the application of this treatment modality. The use of haploidentical donors has in the past been fraught with a greater rate of complications related to both higher rates of GvHD and delayed immunorecovery. Newer transplant regimens appear to have diminished these risks and improved outcomes. We propose using a subablative conditioning regimen followed by post-transplant cyclophosphamide for patients with CGD who do not have an HLA matched donor but whose circumstances necessitate the use of a potentially curative, albeit high-risk treatment modality.

Official Title
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Haploidentical Transplant for Patients With Chronic Granulomatous Disease (CGD) Using Post-Transplant Cyclophosphamide

Conditions
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Chronic Granulomatous Disease

Intervention / Treatment
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* Drug: Sirolimus
* Biological: Donor peripheral blood stem cells.
* Drug: Cyclophosphamide post transplant
* Radiation: Total body 200cGy
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Busulfan


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Must have sufficient complications from underlying disease to warrant undergoing transplantation Ages 2 years - 65 years No appropriate HLA matched donor (available donor has greater than 1 mismatch or the single mismatch is not at DQ for unrelated donors (including cord blood products), or no available 6 out of 6 HLA matched related donor), or patients who may have an unrelated donor, but whose clinical status is such that the time required to obtain an unrelated donor would be life threatening. HLA haploidentical family donor graft available. Ability to comprehend and willingness to sign the informed consent or have a parent/guardian consent if the donor is a minor; assent being obtained from minors as appropriate Must be HIV negative Must not be pregnant (confirmed by a negative serum beta-human chorionic gonadotropin (Beta-hCG) for women of child-bearing potential) or breastfeeding Must be able to stay within one hour s travel of the NIH for the first 3 months after transplantation and have a family member or other designated companion to stay with during the post-transplant period. Must provide a durable power of attorney for health care decisions to an appropriate adult relative or guardian in accordance to NIH Form-200 NIH Durable Power of Attorney for Health Care Decision Making. Where appropriate, subjects must agree to use contraception for 3 months post-transplant EXCLUSION CRITERIA: Major anticipated illness or organ failure incompatible with survival from Allo-transplant Inadequate collection from prospective donors.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 65 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: CGD Recipient<br>CGD patients that will undergo haplo transplantation with post-transplant cyclophosphamide as described | Drug: Sirolimus<br>* For pediatric patients: Begin sirolimus 1 mg/m2 PO q4h for 3 doses, then 1 mg/m2 once a day (QD). For adult patients, begin sirolimus 5 mg PO q4h for 3 doses, then 5 mg once a day (QD). Doses may be adjusted to maintain trough levels between 8-14 ng/ml. Recipients will take sirolimus from Day +5 to at least Day 100 (minimum).<br>* Other names: Rapamycin;Biological: Donor peripheral blood stem cells.<br>* Infuse donor graft.<br>Drug: Cyclophosphamide post transplant<br>* 50 mg/kg/d IV infused over 90 minutes. Day +3 and +4<br>* Other names: Cytoxan post transplant;Radiation: Total body 200cGy<br>* Day -1<br>Drug: Cyclophosphamide<br>* 14.5 mg/kg IV over one hour Day -6 and -5<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 30 mg/m2 over 30 minutes Day -6 through Day -2<br>* Other names: Fludara;Drug: Busulfan<br>* Busulfan 3.2 mg/kg IV once daily over 2-3 hours Day -4,-3,-2<br>* Other names: Busulfex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Efficacy of This Allogeneic Transplant Approach in Reconstituting Normal Hematopoiesis and Reversing the Clinical Phenotype of CGD | Patient will have donor chimerism of greater than 20% and resolution of infection or autoimmunity at end of follow up | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Safety of This Allogeneic HSCT Approach in Patients With CGD Including Transplant Related Toxicity, the Incidence of Acute and Chronic Graft-versus-host Disease, Immune Reconstitution, Overalland Disease-free Survival. | 1. Stable chimerism as indicated by 30-50% myeloid engraftment and 50% lymphoid engraftment as assessed by 1 year post transplant. 2. Immune reconstitution levels with DHR as a marker of normal neutrophil function by 1 year post transplant. 3. GvHD grades of less than 3. | 1 year post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Granulomatous Disease, Halo-Identical Protocol, Transplant