reduced intensity conditioning for hemophagocytic syndromes or selected primary immune deficiencies (bmt ctn 1204)

Conditions: Hemophagocytic Lymphohistiocytosis; Chronic Active Epstein-Barr Virus Infection; Chronic Granulomatous Disease; HIGM-1; Leukocyte Adhesion Deficiency; IPEX

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.

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 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.

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)