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

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.

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.