Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT01998633
First received: October 29, 2013
Last updated: August 1, 2016
Last verified: August 2016
  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
Chronic Active Epstein-Barr Virus Infection
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 CTN #1204)

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • Overall survival (OS) [ Time Frame: Year 1 ] [ Designated as safety issue: Yes ]
    OS at one year post-transplant in patients who receive at least one dose of the preparative regimen.


Secondary Outcome Measures:
  • Sustained Engraftment [ Time Frame: Days 100, 180, 365 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]

    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.

  • Frequency of Transplant-Related Complications [ Time Frame: Day 365 ] [ Designated as safety issue: Yes ]

Enrollment: 46
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)/ 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.
  Eligibility

Ages Eligible for Study:   4 Months to 45 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Patient is ≥ 3 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 [a. Inherited gene mutation associated with HLH: PRF1, UNC13D (MUNC13-2), STXBP2 (MUNC18-2), STX11, RAB27A (Griscelli syndrome, type 2), SH2D1A (XLP1), XIAP (XLP2), LYST (Chediak-Higashi syndrome) - OR - b. Meets clinical criteria for HLH, refractory to therapy according to HLH-94 or HLH-2004 (dexamethasone/etoposide), or recurrent episodes of hyper-inflammation - OR - c. Meets clinical criteria for HLH, without identified gene defects, with affected sibling - OR - decreased or absent NK cell function at the last evaluation, - OR - a history of CNS inflammation as evidenced by pleocytosis in CSF or MRI evidence of hyper-inflammation in the CNS]

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). [Patients must meet all of the following: a. Severe progressive illness, usually with fever, lymphadenopathy and splenomegaly that either began as primary EBV infection or was associated with markedly elevated antibody titers to EBV viral capsid antibody (≥ 1:5120) or early antigen (≥ 1:640), or markedly elevated EBV DNA in the blood; - AND - b. Infiltration of tissues (e.g., lymph nodes, liver, lungs, CNS, bone marrow, eye, skin) with lymphocytes; - AND - c. Elevated EBV DNA, RNA or proteins in affected tissues; - AND - d. The absence of HIV or post-transplant lymphoproliferative disorder]

2C. Chronic granulomatous disease with indication for HCT [a. Oxidative burst < 10% normal with dihydrorhodamine (DHR) assay - AND - b. Documented CGD mutation(s) in gp91phox, p47phox, p67phox, p22phox or p40phox - AND - c. Severe disease as evidenced by one or more of the following: history of one or more potentially life-threatening infections; inflammatory bowel disease; failure to thrive with height <10% for age (unless parent(s) height <10%); or autoimmune complication felt to be linked to CGD]

2D. X-linked Hyper IgM Syndrome (HIGM1) [a. Decreased serum IgG (more than 2 standard deviations below normal for age) - AND - b. Mutation in CD40LG - OR - family history of maternally related males with HIGM1]

2E. IPEX Syndrome [a. Absent FOXP3+ CD4+ T cells - OR - abnormal function of FOXP3+CD4+ T cells - AND - b. Disease-associated mutation in FoxP3 (bi-allelic in females) - OR - family history of maternally related males with clinical diagnosis of IPEX]

2F. Severe Leukocyte Adhesion Deficiency, type I (LAD-I) [a. Decreased CD18 expression on neutrophils (<5% normal for age) - AND - b. Mutation of ITGB2 - OR - absence of ITGB2 mRNA in leukocytes]

3. Lansky or Karnofsky performance status ≥ 50%.

4. The patient's donor must be willing and able to give bone marrow stem cells and be:

a. An unaffected sibling donor who is a 6/6 match at HLA-A and -B (intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) OR b. An unaffected related donor (other than sibling) who is a 7/8 or 8/8 match for HLA-A, -B, -C (at intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) OR c. An unrelated donor who is a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 (at high resolution using DNA-based typing).

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/1.73m^2
  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 one 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 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 receiving appropriate antimicrobials and experiencing 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 (or prior to initiating the preparative regimen).
    3. Pregnant or breastfeeding.
    4. Seropositive for human immunodeficiency virus (HIV).
    5. Alemtuzumab within 2 weeks of enrollment.
    6. History of prior or current malignancy, especially malignancies with a likelihood of relapse and progression, with the exception of (1) EBV-associated lymphomas related to immune deficiency or lymphomas associated with X-linked LPD in a good remission, as they are unlikely to relapse after treatment; (2) Resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01998633

  Show 22 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Investigators
Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin
  More Information

Additional Information:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT01998633     History of Changes
Other Study ID Numbers: BMTCTN1204  2U10HL069294-11  5U24CA076518 
Study First Received: October 29, 2013
Last Updated: August 1, 2016
Health Authority: United States: Federal Government
United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Findings will be published in a manuscript.

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:
Syndrome
Virus Diseases
Tissue Adhesions
Lymphohistiocytosis, Hemophagocytic
Immunologic Deficiency Syndromes
Granulomatous Disease, Chronic
Epstein-Barr Virus Infections
Granuloma
Disease
Pathologic Processes
Cicatrix
Fibrosis
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Immune System Diseases
Phagocyte Bactericidal Dysfunction
Leukocyte Disorders
Hematologic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Herpesviridae Infections
DNA Virus Infections
Tumor Virus Infections
Lymphoproliferative Disorders

ClinicalTrials.gov processed this record on September 29, 2016