Clinical Trial: Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Reduced-Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (RICHI) (BMT CTN #1204)

Brief Summary: 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.

Detailed Summary: 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)/ Matched Unrelated Donor (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 human leukocyte antigen (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.
Sponsor: Medical College of Wisconsin

Current Primary Outcome: Overall survival (OS) [ Time Frame: Year 1 ]

OS at one year post-transplant in patients who receive at least one dose of the preparative regimen.


Original Primary Outcome: Overall survival at 1 year [ Time Frame: 1 year ]

Current Secondary Outcome:

  • Sustained Engraftment [ Time Frame: Days 100, 180, 365 ]
    Sustained engraftment will be considered to have occurred in the absence of primary graft failure: < 5% donor chimerism by Day +42; second stem cell infusion: DLI (except in the case of donor CTLs given for infection control) or second HCT following original HCT; and secondary graft failure: < 5% donor chimerism following original engraftment.
  • HLH Reactivation [ Time Frame: Year 1 ]

    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.

    Central nervous system (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 Cerebrospinal fluid (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.

  • Immune Reconstitution [ Time Frame: Days 100 and 365 ]
    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.
  • Neutrophil Engraftment [ Time Frame: Day 56 ]
    Time to absolute neutrophil count (ANC) engraftment is defined as the first of three measurements on different days that the patient has an absolute neutrophil count of ≥ 500/uL following conditioning regimen induced nadir.
  • Platelet Engraftment [ Time Frame: Day 56 ]
    Platelet engraftment is defined as the first day of a minimum of three measurements on different days that the patient has achieved a platelet count > 20,000 AND the patient is platelet transfusion independent for a minimum of seven days following conditioning regimen induced nadir.
  • Cumulative Incidence of Grade Acute GVHD [ Time Frame: Day 100 ]
    The cumulative incidence of grade II-IV and grade III-IV acute GVHD will be assessed according to the BMT CTN Manual of Procedures (MOP).
  • Cumulative Incidence of Chronic GVHD [ Time Frame: Day 365 ]
    Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.
  • Frequency of Transplant-Related Complications [ Time Frame: Day 365 ]


Original Secondary Outcome:

  • Sustained Engraftment [ Time Frame: Measured at day 28, 56, 84, 100, 180, 365 ]
  • HLH Reactivation [ Time Frame: 1 year ]

    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 ]

    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 ]
  • Cumulative Incidence of Platelet Engraftment [ Time Frame: Measured at Day +365 ]
  • Cumulative Incidence of Grade II-IV Acute GVHD [ Time Frame: Measured at Day +100 ]
  • Cumulative Incidence of Grade III-IV Acute GVHD [ Time Frame: Measured at Day +100 ]
  • Cumulative Incidence of Chronic GVHD [ Time Frame: Measured at Day +365 ]
  • Frequency of Transplant-Related Complications [ Time Frame: Measured at Day +365 ]


Information By: Medical College of Wisconsin

Dates:
Date Received: October 29, 2013
Date Started: December 2013
Date Completion: December 2018
Last Updated: February 7, 2017
Last Verified: February 2017