Haploidentical Transplant for People With Chronic Granulomatous Disease Using Post Transplant Cyclophosphamide
Study Details
Study Description
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.
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get chemotherapy, radiation, and other medicines.
-
get an intravenous (IV) catheter in their chest.
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have the transplant.
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get more medicines and standard supportive care.
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have blood drawn frequently.
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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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: CGD Recipient CGD patients that will undergo haplo transplantation with post-transplant cyclophosphamide as described |
Drug: 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).
Other Names:
Biological: Donor peripheral blood stem cells.
Infuse donor graft.
Drug: Cyclophosphamide post transplant
50 mg/kg/d IV infused over 90 minutes. Day +3 and +4
Other Names:
Radiation: Total body 200cGy
Day -1
Drug: Cyclophosphamide
14.5 mg/kg IV over one hour Day -6 and -5
Other Names:
Drug: Fludarabine
30 mg/m2 over 30 minutes Day -6 through Day -2
Other Names:
Drug: Busulfan
Busulfan 3.2 mg/kg IV once daily over 2-3 hours Day -4,-3,-2
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
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.
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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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Principal Investigator: Elizabeth M Kang, M.D., National Institute of Allergy and Infectious Diseases (NIAID)
Study Documents (Full-Text)
More Information
Publications
- Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, BolaƱos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. doi: 10.1016/j.bbmt.2008.03.005.
- Munchel A, Kesserwan C, Symons HJ, Luznik L, Kasamon YL, Jones RJ, Fuchs EJ. Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-transplantation cyclophosphamide. Pediatr Rep. 2011 Jun 22;3 Suppl 2:e15. doi: 10.4081/pr.2011.s2.e15.
- Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: current status and future perspectives. Blood. 2011 Dec 1;118(23):6006-17. doi: 10.1182/blood-2011-07-338822. Epub 2011 Sep 14. Review.
- 150007
- 15-I-0007
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | CGD Recipient |
---|---|
Arm/Group Description | 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 |
Period Title: Overall Study | |
STARTED | 7 |
COMPLETED | 7 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | CGD Recipient |
---|---|
Arm/Group Description | 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 |
Overall Participants | 7 |
Age (Count of Participants) | |
<=18 years |
3
42.9%
|
Between 18 and 65 years |
4
57.1%
|
>=65 years |
0
0%
|
Age (years) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [years] |
19.42
(4.8)
|
Sex: Female, Male (Count of Participants) | |
Female |
2
28.6%
|
Male |
5
71.4%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
2
28.6%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
0
0%
|
White |
2
28.6%
|
More than one race |
1
14.3%
|
Unknown or Not Reported |
2
28.6%
|
Region of Enrollment (Count of Participants) | |
United States |
6
85.7%
|
India |
1
14.3%
|
Infection present (Count of Participants) | |
Count of Participants [Participants] |
3
42.9%
|
Autoimmunity present (Count of Participants) | |
Count of Participants [Participants] |
4
57.1%
|
Outcome Measures
Title | To Determine the Efficacy of This Allogeneic Transplant Approach in Reconstituting Normal Hematopoiesis and Reversing the Clinical Phenotype of CGD |
---|---|
Description | Patient will have donor chimerism of greater than 20% and resolution of infection or autoimmunity at end of follow up |
Time Frame | 5 years |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | CGD Recipient |
---|---|
Arm/Group Description | 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 |
Measure Participants | 7 |
Greater than 20% donor chimerism |
7
100%
|
Resolution of inflammation or infection |
7
100%
|
Title | 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. |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | CGD Recipient |
---|---|
Arm/Group Description | 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 |
Measure Participants | 7 |
Number of patients with stable chimerism at 1 year |
6
85.7%
|
Patients with normal DHR at 1 year |
6
85.7%
|
Patients with Acute (Grade 3 or higher) GvHD |
3
42.9%
|
Patients with Chronic GvHD |
0
0%
|
Overall Survival |
5
71.4%
|
Disease Free Survival |
5
71.4%
|
Adverse Events
Time Frame | Adverse Events were collected over 5 years (2015 to 2019) | |
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | CGD Recipient | |
Arm/Group Description | 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 | |
All Cause Mortality |
||
CGD Recipient | ||
Affected / at Risk (%) | # Events | |
Total | 2/7 (28.6%) | |
Serious Adverse Events |
||
CGD Recipient | ||
Affected / at Risk (%) | # Events | |
Total | 3/7 (42.9%) | |
Blood and lymphatic system disorders | ||
Post transplant lymphoproliferative disease | 1/7 (14.3%) | 1 |
Immune system disorders | ||
Severe Acute GvHD | 3/7 (42.9%) | 3 |
Renal and urinary disorders | ||
Hemorrhagic Cystitis | 1/7 (14.3%) | 1 |
Other (Not Including Serious) Adverse Events |
||
CGD Recipient | ||
Affected / at Risk (%) | # Events | |
Total | 7/7 (100%) | |
Immune system disorders | ||
Mild GvHD | 7/7 (100%) | 7 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Elizabeth Kang |
---|---|
Organization | NIAID |
Phone | 3014027567 |
ekang@niaid.nih.gov |
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