Chronic Granulomatous Disease
Conditions
Keywords
Chronic Granulomatous Disease, Halo-Identical Protocol, Transplant
Brief summary
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
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.
Interventions
DRUGSirolimus
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).
BIOLOGICALDonor peripheral blood stem cells.
Infuse donor graft.
DRUGCyclophosphamide post transplant
50 mg/kg/d IV infused over 90 minutes. Day +3 and +4
RADIATIONTotal body 200cGy
Day -1
DRUGCyclophosphamide
14.5 mg/kg IV over one hour Day -6 and -5
DRUGFludarabine
30 mg/m2 over 30 minutes Day -6 through Day -2
DRUGBusulfan
Busulfan 3.2 mg/kg IV once daily over 2-3 hours Day -4,-3,-2
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Efficacy of This Allogeneic Transplant Approach in Reconstituting Normal Hematopoiesis and Reversing the Clinical Phenotype of CGD | 5 years | Patient will have donor chimerism of greater than 20% and resolution of infection or autoimmunity at end of follow up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 year post transplant | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CGD Recipient CGD patients that will undergo haplo transplantation with post-transplant cyclophosphamide as described
Sirolimus: 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).
Donor peripheral blood stem cells.: Infuse donor graft.
Cyclophosphamide post transplant: 50 mg/kg/d IV infused over 90 minutes. Day +3 and +4
Total body 200cGy: Day -1
Cyclophosphamide: 14.5 mg/kg IV over one hour Day -6 and -5
Fludarabine: 30 mg/m2 over 30 minutes Day -6 through Day -2
Busulfan: Busulfan 3.2 mg/kg IV once daily over 2-3 hours Day -4,-3,-2 | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | CGD Recipient |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 19.42 years STANDARD_DEVIATION 4.8 |
| Autoimmunity present | 4 Participants |
| Infection present | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment India | 1 Participants |
| Region of Enrollment United States | 6 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 3 / 7 |
Outcome results
Primary
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
Time frame: 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CGD Recipient | To Determine the Efficacy of This Allogeneic Transplant Approach in Reconstituting Normal Hematopoiesis and Reversing the Clinical Phenotype of CGD | Greater than 20% donor chimerism | 7 Participants |
| CGD Recipient | To Determine the Efficacy of This Allogeneic Transplant Approach in Reconstituting Normal Hematopoiesis and Reversing the Clinical Phenotype of CGD | Resolution of inflammation or infection | 7 Participants |
Secondary
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.
Time frame: 1 year post transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CGD Recipient | 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. | Number of patients with stable chimerism at 1 year | 6 Participants |
| CGD Recipient | 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. | Patients with normal DHR at 1 year | 6 Participants |
| CGD Recipient | 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. | Patients with Acute (Grade 3 or higher) GvHD | 3 Participants |
| CGD Recipient | 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. | Patients with Chronic GvHD | 0 Participants |
| CGD Recipient | 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. | Overall Survival | 5 Participants |
| CGD Recipient | 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. | Disease Free Survival | 5 Participants |