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Alemtuzumab

Participants will undergo a non-myeloablative allogeneic 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)

Hematopoietic Stem Cell Transplant

Mary Horowitz, MD, MS

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.

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

Reduced-Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (RICHI) (BMT CTN #1204)

Findings will be published in a manuscript.

Overall survival is defined as survival of death from any cause.

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.

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 ≥ 500x10\^6/liter following conditioning regimen induced nadir.

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 / microliter AND the patient is platelet transfusion independent for a minimum of seven days following conditioning regimen induced nadir.

Sustained engraftment is defined as the occurrence of whole blood donor chimerism \> 5% by Day 42 accompanied by the absence of any primary or secondary graft failure. Primary graft failure is defined as \< 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. Secondary graft failure is defined as \< 5% donor chimerism following initial engraftment.

Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:

Skin stage:

0: No rash

1. Rash \<25% of body surface area
2. Rash on 25-50% of body surface area
3. Rash on \> 50% of body surface area
4. Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level)\*:

0: \<2 mg/dL

1. 2-3 mg/dL
2. 3.01-6 mg/dL
3. 6.01-15.0 mg/dL
4. \>15 mg/dL

GI stage\*:

0: No diarrhea or diarrhea \<500 mL/day

1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD
2. Diarrhea 1000-1499 mL/day
3. Diarrhea \>1500 mL/day
4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.

GVHD grade:

0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4

Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.

Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification.

National Heart, Lung, and Blood Institute (NHLBI)

Blood and Marrow Transplant Clinical Trials Network

National Cancer Institute (NCI)

National Marrow Donor Program

Medical College of Wisconsin

Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.

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)

Participants with Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH)

Participants with other primary immune deficiencies, including chronic active EBV disease, chronic granulomatous disease, hyper-immunoglobulin M syndrome, and immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome

Other Primary Immune Deficiencies (PID)

Total

Age, Customized

Sex: Female, Male

Race (NIH/OMB)

KPS describes patient-perceived global quality of life and functioning on a scale of 0-100.

100: No evidence of disease; 90: Normal activity. Minor signs or symptoms of disease; 80: Normal activity with effort. Some signs or symptoms of disease; 70: Cares for self. Unable to continue normal activity; 60: Needs occasional assistance, but cares for most personal needs; 50: Needs considerable assistance and medical care; 40: Disabled. Needs special care and assistance; 30: Severely disabled. Hospital admission indicated; 20: Very sick. Active supportive therapy needed; 10: Moribund; 0: Dead

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)	NCT01998633	Hemophagocytic ... Chronic Active ... Chronic Granulo... HIGM-1 Leukocyte Adhes... IPEX	Hematopoietic S...	4 Months - 45 Years	Medical College of Wisconsin
Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)	NCT01998633	Hemophagocytic ... Chronic Active ... Chronic Granulo... HIGM-1 Leukocyte Adhes... IPEX	Hematopoietic S...	4 Months - 45 Years	Medical College of Wisconsin

Spots Global Cancer Trial Database for hyperimmunoglobulin m syndrome (hyper igm)