High Dose Peripheral Blood Stem Cell Transplantation With Post Transplant Cyclophosphamide for Patients With Chronic Granulomatous Disease
Study Details
Study Description
Brief Summary
Chronic granulomatous disease (CGD) affects white blood cell function. Currently, the only curative treatment is bone marrow transplant to replace the abnormal stem cells with new ones (donor cells) capable of making a normal immune system. Transplant problems include graft versus host disease (GvHD) and graft rejection. With GvHD, donor cells attack the recipient s normal tissue. Researchers want to use preparation drugs and a high cell dose to increase graft success. They want to use 2 immunosuppressive drugs (cyclophosphamide and sirolimus) to lessen the risk of GvHD.
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| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 1/Phase 2 |
Detailed Description
Chronic Granulomatous Disease (CGD) is an inherited disorder resulting from a failure to produce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, necessary for protection against a number of infectious organisms. Patients are subject to recurrent infections and inflammatory complications. The current management of these participants is limited to close surveillance for infections, administration of prophylactic antimicrobials, and rapid and aggressive treatment of suspected and documented infections with broad-spectrum antibiotics. Although often effective, these treatments can require long hospitalizations, impacting on the overall quality of life significantly, and lead to significant morbidity, such as renal failure and deafness. CGD patients have auto
inflammation that may manifest as inflammatory bowel disease, hypoxic lung inflammation, and/or liver nodular regenerative hyperplasia with venopathy as examples.
Currently, the only available cure for these disorders is bone marrow transplantation, which most commonly uses a human leukocyte antigen (HLA)-matched related sibling as the donor (allogeneic stem sell transplantation). However, as only 30% of participants in the general population have an HLA- matched related sibling, allogeneic related transplantation is often not an option, resulting in the need for matched unrelated donor (MUD) transplantation. The National Marrow Donor Program (NMDP) serves as both a national registry of volunteers who are willing to donate progenitor cells to eligible recipients as well as a repository of cord blood products. Despite continued improvement in the use of transplantation schemas including the development of nonmyeloablative regimens there remain significant morbidity and mortality associated with transplantation, in particular, graft versus host disease (GvHD) and graft rejection. CGD with severe autoinflammation manifested as C-reactive protein (CRP) >100 appear to be at a significantly increased risk of severe engraftment syndrome and/or GvHD, based on our results to date and will be therefore be excluded from this protocol.
GvHD is a result of the graft recognizing host antigens as foreign, typically in the presence of inflammation, and results in a type of iatrogenic autoimmune disease. For participants with non-malignant diseases, the aim of the transplant is solely to replace the defective or deficient cell population. Furthermore, as a graft versus tumor effect is not required, regimens designed to establish tolerance induction and/or stable mixed chimerism may be preferable for cure in this participant population; therefore, alternate transplant strategies can and should be used to further suppress the development of any GvHD effects.
In a prior protocol we observed low rates of GvHD, using a nonmyeloablative conditioning regimen but had significant rates of graft failure and/or loss. To improve upon our results we therefore propose to increase the target cell dose to be infused and use post transplant cyclophosphamide to mitigate the increased risk of GvHD.
For the patients with an HLA matched sibling donor (Group 1-Sibling Related) we propose using a busulfan-based, nonmyeloablative conditioning regimen combined with Alemtuzumab (Campath-1H, Campath ) an immunosuppressive monoclonal antibody currently approved by the U.S. Food and Drug Administration (FDA) as a single treatment for patients with B-cell chronic lymphocytic leukemia; however, for this protocol we are using it for its mechanism of action as an immunosuppressive agent. For GvHD prophylaxis we will use post-transplant cyclophosphamide (Cytoxan ) and sirolimus (Rapamune ).
For patients with only a MUD (Group 2-MUD) we will use a similar conditioning regimen, with a few modifications including the addition of total body irradiation (TBI) to enhance immune suppression (but with lower dose of busulfan),due to the increased risk of graft rejection with HLA-matched but unrelated cells, along with the posttransplant cyclophosphamide. We will compare the results obtained here to our previous clinical trial which did not use post transplant Cytoxan and where the cell dose infused was lower than the targeted dose of 10 million CD34+ hematopoietic stem cells/kg body weight in this study, but did use the same conditioning regimen.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: 1 There is only one treatment arm for this study |
Drug: Alentuzumab (Campath)
Transplant Conditioning Drug: Monoclonal antibody that targets recipient and donor T-cells to prevent graft verses host disease. Not an IND. This is a well studied drug, and is not under an IND.
Drug: Busulfan IV
Transplant Conditioning Drug: Chemotherapy to create space in the patient's bone marrow so that the donor peripheral blood stem cells can repopulate in the patient's bone marrow. This is a well studied drug, and is not under an IND.
Drug: Sirolimus
Immunosuppressant to prevent donor peripheral blood stem cell rejection and graft versus host disease. This is a well studied drug, and is not under an IND.
Drug: Cyclophosphamide
Post transplant cyclophosphamide given to prevent graft verses host disease. This is a well studied drug, and is not under an IND.
Radiation: Total Body Irradiation
Transplant Conditioning Total Body Radiation (300cGy in 2 fractionated doses), given only to patient receiving matched unrelated donor cells, to create space in the patient's bone marrow so that the donor peripheral blood stem cells can repopulate in the patient's bone marrow.
Biological: Peripheral blood stem cells
Donor Peripheral blood stem cells, either matched unrelated donor or matched related relative to replace the patient's immune cells with functional immune cells. The peripheral blood stem cells are not regulated by the FDA.
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Outcome Measures
Primary Outcome Measures
- To determine engraftment rates with the use of high cell doses, without increasing the risk of GvHD by using post- transplant cyclophosphamide and sirolimus in conjunction with a busulfan- based conditioning regimen. We will compare the incidenc... [5 years]
This study is still recruiting patients.
Secondary Outcome Measures
- To measure the engraftment rate and the engraftment kinetics using such a regimen [5 years]
This study is still recruiting patients
- To assess the level and kinetics of immune reconstitution (via chimerism) when using post- transplant cyclophosphamide [5 years]
This study is still recruiting patients
- To further elucidate the factors involved in the development of GvHD and graft rejection/failure [5 years]
This study is still recruiting patients
Eligibility Criteria
Criteria
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INCLUSION CRITERIA:
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Must have confirmed Chronic Granulomatous Disease.
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Must have sufficient complications from underlying disease to warrant undergoing transplantation (either a history of or ongoing inflammation/CGD related autoimmunity OR a CGD related infection while on prophylaxis) OR or have a Quartile 1 and/or 2 residual oxidase production level.
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Ages 4 years - 65 years
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HLA-matched family donor graft or an HLA matched unrelated peripheral blood stem cell (PBSC) graft (10/10 or 9/10 mismatch) available
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Must be HIV negative
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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.
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Must provide a durable power of attorney for health care decisions to an appropriate adult relative or guardian in accordance to NIH -200 NIH Durable Power of Attorney for Health Care Decision Making .
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If of child-bearing potential, must agree to consistently use contraception from one month prior to, and throughout, study participation, and for 3 months post-study.
Acceptable forms of contraception are:
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Contraceptive pills or patch, Norplant , Depo-Provera , or other FDA-approved contraceptive method
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Male partner has previously undergone a vasectomy.
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Male participants will be advised to consistently use contraception throughout study participation and for 3 months post-transplant.
EXCLUSION CRITERIA:
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Eastern Cooperative Oncology Group (ECOG) or equivalent performance status greater than or equal to 3 (See Supportive Care guidelines, available at http://intranet.cc.nih.gov/bmt/clinicalcare)
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Left ventricular ejection fraction < 40%
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Transaminases > 5x upper limit of normal based on the participant s clinical situation and at the discretion of the investigator
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Psychiatric disorder or mental deficiency severe enough as to make compliance with the HSCT treatment unlikely, and/or making regulatorily and legally effective informed consent impossible
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Major anticipated illness or organ failure incompatible with survival from AlloPBSC transplant
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Pregnant or lactating
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HIV positive
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Uncontrolled seizure disorder
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Individuals older than 65 are excluded. It is known from standard transplantation that these participants have a higher risk of morbidity and mortality related to transplantation. Given the investigational nature of this protocol, the risk benefit ratio is not warranted to include these participants at this time.
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Any condition or circumstance which the PI feels would create difficulty in maintaining compliance with the requirements of this protocol.
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Individuals who are not willing to submit their information as part of the Alemtuzumab (Campath) Distribution Program application or participants whom the Distribution Program committee has determined are not qualified to receive alemtuzumab.
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Patients with a CRP greater than 100 mg/L within 30 days of anticipated transplant.
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)
None provided.More Information
Additional Information:
Publications
- Horwitz ME, Barrett AJ, Brown MR, Carter CS, Childs R, Gallin JI, Holland SM, Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001 Mar 22;344(12):881-8.
- Kang EM, Hsieh MM, Metzger M, Krouse A, Donahue RE, Sadelain M, Tisdale JF. Busulfan pharmacokinetics, toxicity, and low-dose conditioning for autologous transplantation of genetically modified hematopoietic stem cells in the rhesus macaque model. Exp Hematol. 2006 Feb;34(2):132-9.
- Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S, Peggs K, Verfuerth S, Pettengell R, Marsh JC, Schey S, Mahendra P, Morgan GJ, Hale G, Waldmann H, de Elvira MC, Williams CD, Devereux S, Linch DC, Goldstone AH, Mackinnon S. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood. 2000 Oct 1;96(7):2419-25.
- 160032
- 16-I-0032