Reduced Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (PIDs) (BMT Clinical Trials Network 1204) (RICHI)

This study is not yet open for participant recruitment.
Verified November 2013 by Medical College of Wisconsin
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01998633
First received: October 29, 2013
Last updated: November 25, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Hemophagocytic Lymphohistiocytosis
CAEBV
Chronic Granulomatous Disease
HIGM-1
Leukocyte Adhesion Deficiency
IPEX
Biological: Hematopoietic Stem Cell Transplant
Phase 2

Study Type: Interventional
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)

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • Overall survival at 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 35
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)
Arms Assigned Interventions
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.

  • Alemtuzumab 0.2mg/kg Day-14,-13,-12,-11,-10
  • Fludarabine 30 mg/m2 on Day -8,-7,-6,-5,-4
  • Melphalan 140mg/m2 on Day -3

The GVHD prophylaxis will consist of the following:

  • Cyclosporine on Day -3 to Day +100, maintaining a level of 250-500 ng/mL, then taper to Day +180.
  • Methylprednisolone 2 mg/kg/day on Day -2 and -1, 1 mg/kg/day on Day 0 to Day +28, then taper over 1 month. Oral prednisone may be substituted starting on Day 0 (1.2 mg/kg/day)

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   4 Months to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient is ≥ 4 months and ≤ 45 years of age at time of enrollment.
  2. Meets criteria for one of the following immune disorders (2A-2F) requiring HCT:

2A. HLH or related disorder with indication for HCT. 2B. CAEBV: Patients with chronic EBV infection (CAEBV) with or without associated lymphoma (in complete remission) or active HLH. Note that this diagnosis is distinct from post-transplant lymphoproliferative disorder/ EBV-associated lymphoproliferative disease (PTLD/LPD).

2C. Chronic granulomatous disease with indication for HCT. 2D. X-linked Hyper IgM Syndrome (HIGM1). 2E. IPEX Syndrome. 2F. Severe Leukocyte Adhesion Deficiency, type I (LAD-I). 3. Lansky or Karnofsky performance status ≥ 50%. 4. Human Leukocyte Antigen (HLA) typing of related donors must be a 6/6 match for HLA-A and -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). Unrelated donors must be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 (at high resolution using DNA-based typing). Only bone marrow stem cells are allowed.

5 Patient must have adequate organ function as measured by:

  1. Cardiac: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction (LVSF) > 26% by echocardiogram.
  2. Renal: Calculated or radioisotope Glomerular filtration rate (GFR) > 50 mL/min/1.73m2
  3. Hepatic: Adequate liver function: serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory (with the exceptions of isolated hyperbilirubinemia due to Gilbert's syndrome, or hyperbilirubinemia as the result of liver inflammation in the setting of persistent, active HLH); Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 10x upper limit of normal as per local laboratory (with the exception of elevated transaminase levels as the result of liver inflammation in the setting of persistent, active HLH).
  4. Pulmonary: Patient may not be on mechanical ventilation support or have progressive pulmonary infection at the time of transplant; Pulmonary Function Testing (PFT) with Forced Expiratory Volume (in 1 second) (FEV1) > 50% of normal and Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) corrected for Hgb > 50% of normal. Patients unable to undergo PFTs should have stable respiratory status with Saturated Oxygen (SaO2) > 90% on a maximum of 2L/min supplemental oxygen.

    6. Signed informed consent.

    Exclusion Criteria:

    1. Hematopoietic stem cell transplant within 6 months of enrollment.
    2. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement) at time of enrollment. We recognize that patients with CAEBV may have ongoing EBV viremia at the time of initiating transplant therapy, but other patients should have no uncontrolled bacterial, viral or fungal infections at the time of enrollment.
    3. Pregnant or breastfeeding.
    4. Seropositive for human immunodeficiency virus (HIV).
    5. Alemtuzumab within 2 weeks of enrollment.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01998633

Contacts
Contact: Linda Johnson 301-251-1161 ext 2834 ljohnson@emmes.com

  Show 23 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
Blood and Marrow Transplant Clinical Trials Network
Investigators
Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin
  More Information

Additional Information:
No publications provided

Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01998633     History of Changes
Other Study ID Numbers: BMTCTN1204, 2U10HL069294-11
Study First Received: October 29, 2013
Last Updated: November 25, 2013
Health Authority: United States: Federal Government

Keywords provided by Medical College of Wisconsin:
Hemophagocytic lymphohistiocytosis
Chronic Active EBV
Chronic Granulomatous Disease
Hyperimmunoglobulin M Syndrome (Hyper IGM)
Leukocyte Adhesion Deficiency
IPEX
Hematopoietic Stem Cell Transplant (HSCT)
Non-Myeloablative Transplant (NST)
Reduced-Intensity Conditioning (RIC)

Additional relevant MeSH terms:
Granulomatous Disease, Chronic
Tissue Adhesions
Lymphohistiocytosis, Hemophagocytic
Hyper-IgM Immunodeficiency Syndrome, Type 1
Granuloma
Cicatrix
Fibrosis
Pathologic Processes
Phagocyte Bactericidal Dysfunction
Leukocyte Disorders
Hematologic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Immunologic Deficiency Syndromes
Immune System Diseases
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Hyper-IgM Immunodeficiency Syndrome
Dysgammaglobulinemia
Blood Protein Disorders
Lymphoproliferative Disorders

ClinicalTrials.gov processed this record on April 17, 2014