Reduced Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (PIDs) (BMT Clinical Trials Network 1204) (RICHI)
HLH, HLH-related disorders, Chronic Granulomatous (CGD), HIGM1, Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) and severe LAD-I represent primary immune disorders that are typically fatal without Hematopoietic Cell Transplant (HCT). However, transplant is often complicated by inflammation, infection and other co-morbidities. In addition, these disorders have been shown to be cured with partial chimerism, making them an ideal target for the use of reduced intensity approaches, where a portion of patients may not achieve full donor chimerism, but instead achieve stable mixed chimerism. Reduced-intensity conditioning strategies have demonstrated improved survival with decreased Treatment Related Mortality (TRM) in institutional series for patients with HLH (Cooper et al., 2006; Marsh et al., 2010; Marsh et al., 2011). However, graft loss and unstable chimerism remain challenges. An institutional case series from Cincinnati Children's Hospital demonstrated full or high-level chimerism and improved durable engraftment using intermediate (Day -14) timing alemtuzumab (Marsh et al., 2013b). This study aims to test the efficacy of the Intermediate RIC strategy in a prospective multi-center study including HLH as well as other primary immunodeficiencies where allogeneic transplant with RIC has been shown to be feasible and stable chimerism is curative.
Chronic Granulomatous Disease
Leukocyte Adhesion Deficiency
Biological: Hematopoietic Stem Cell Transplant
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||REDUCED-INTENSITY CONDITIONING FOR CHILDREN AND ADULTS WITH HEMOPHAGOCYTIC SYNDROMES OR SELECTED PRIMARY IMMUNE DEFICIENCIES (RICHI)(BMT Clinical Trials Network (CTN) 1204)|
- Overall survival at 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
- Sustained engraftment [ Time Frame: Measured at day 28, 56, 84, 100, 180, 365 ] [ Designated as safety issue: No ]
- HLH Reactivation [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Systemic HLH Reactivation: Post-transplant HLH reactivation is defined by clinical and lab evidence of pathologic inflammation (persistent fever, progressive cytopenias, rising ferritin and soluble IL2Rα, decreasing fibrinogen, hepatosplenomegaly, end-organ damage) not attributable to other causes.
CNS HLH Reactivation: Reactivation of CNS inflammation in patients with HLH may present with or without altered mental status and is defined by pleocytosis in CSF or an MRI consistent with CNS inflammation not attributable to other causes.
To assess the incidence of reactivation, cumulative incidence curves will be computed along with a 95% confidence interval. Death prior to reactivation will be considered as a competing risk. Death due to reactivation will be noted.
- Immune Reconstitution [ Time Frame: Baseline (pre-conditioning) Day 100 and Day 365 ] [ Designated as safety issue: No ]
Recovery of lymphocyte subpopulations: Absolute number of CD3, CD4, CD8, CD16+56 and CD19 cells will be measured by flow cytometry. Immunoglobulin levels (IgG, IgA and IgM) will alsRecovery of lymphocyte subpopulations: Absolute number of CD3, CD4, CD8, CD16+56 and CD19 cells will be measured by flow cytometry. Immunoglobulin levels (IgG, IgA and IgM) will also be quantified (at baseline prior to conditioning, Day +100 and Day +365).
Correction of Immune Defects: Disease-specific studies will be tested prior to conditioning, on Day +100 and Day +365, per underlying diagnosis.
Summary statistics for absolute number of CD3, CD4, CD8, CD16+56, and CD19 cells and immunoglobulin levels IgG, IgA and IgM will be reported at baseline, Day +100 and Day +365.
- Cumulative Incidence of Neutrophil Engraftment [ Time Frame: Measured at Day +42 ] [ Designated as safety issue: No ]
- Cumulative Incidence of Platelet Engraftment [ Time Frame: Measured at Day +365 ] [ Designated as safety issue: No ]
- Cumulative Incidence of Grade II-IV Acute GVHD [ Time Frame: Measured at Day +100 ] [ Designated as safety issue: No ]
- Cumulative Incidence of Grade III-IV Acute GVHD [ Time Frame: Measured at Day +100 ] [ Designated as safety issue: No ]
- Cumulative Incidence of Chronic GVHD [ Time Frame: Measured at Day +365 ] [ Designated as safety issue: No ]
- Frequency of Transplant-Related Complications [ Time Frame: Measured at Day +365 ] [ Designated as safety issue: Yes ]
|Study Start Date:||December 2013|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
Experimental: Hematopoietic Stem Cell Transplant
Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.
Biological: Hematopoietic Stem Cell Transplant
NOTE: The - sign is the number of days before the transplant and the + sign is the number of days after the transplant.
The GVHD prophylaxis will consist of the following:
The primary goal of this Phase II clinical trial is to determine the one-year overall survival of patients treated for immune deficiencies including HLH, HLH-like disorders, CGD, HIGM1, IPEX syndrome, and severe LAD-I with Matched Related Donor (MRD)/MUD bone marrow transplant using a reduced-intensity conditioning strategy including intermediate-timing of alemtuzumab. The donor choice is an unaffected related bone marrow donor who is a 6/6 match at HLA-A, -B (intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) OR a 7/8 or 8/8 match for HLA-A, -B, -C and -DRB1 (at high resolution using DNA-based typing), OR an unrelated bone marrow donor who is a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 (at high resolution using DNA-based typing). The transplant conditioning regimen will include fludarabine, melphalan, and alemtuzumab starting at Day -14 (Flu/Mel/Alem). Graft Versus Host Disease (GVHD) prophylaxis will consist of cyclosporine and corticosteroids through engraftment. Post-transplant supportive care will include infection surveillance and prophylaxis, and disease-specific supportive care.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01998633
|Contact: Linda Johnson||301-251-1161 ext email@example.com|
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|Study Director:||Mary Horowitz, MD, MS||Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin|