Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
Condition: Hemophagocytic Lymphohistiocytosis; Chronic Active Epstein-Barr Virus Infection; Chronic Granulomatous Disease; HIGM-1; Leukocyte Adhesion Deficiency; IPEX
MeSH terms: Epstein-Barr Virus Infections; Granulomatous Disease, Chronic; Lymphohistiocytosis, Hemophagocytic; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes
Intervention: Hematopoietic Stem Cell Transplant
Intervention description: 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)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 47.0
Sex: All
Minimum age: 4 Months
Maximum age: 45 Years
Healthy volunteers: No
Keywords: 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)

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.
    

Eligibility 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.