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.

• Hematopoietic Stem Cell Transplant (Biological): 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)

Primary outcomes

• Percentage of Participants With Overall Survival (OS) [1 year and 18 months post-transplant]: Overall survival is defined as survival of death from any cause.

Secondary outcomes

• Percentage of Participants With Overall Survival (OS) by Disease Type [1 year and 18 months post-transplant]: Overall survival is defined as survival of death from any cause.
• Percentage of HLH Participants With HLH Reactivation Post-Transplant [1 year post-transplant]: 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.
• Percentage of Participants With Neutrophil Engraftment [Day 42 post-transplant]: 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.
• Percentage of Participants With Platelet Engraftment [Day 100 post-transplant]: 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.
• Percentage of Participants Alive With Sustained Engraftment [1 year post-transplant]: 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.
• Percentage of Participants Alive With Sustained Engraftment by Disease Type [1 year post-transplant]: 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.
• Number of Participants With Acute Graft-Versus-Host Disease (GVHD) [1 year post-transplant]: 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
• Percentage of Participants With Grade II-IV and Grade III-IV Acute GVHD [Day 100 and 6 months post-transplant]: 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
• Number of Participants With Chronic GVHD [1 year post-transplant]: Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.
• Percentage of Participants With Chronic GVHD [1 year post-transplant]: 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.

Sex: All, ages: 4 Months to 45 Years

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.

Participant flow

Outcome results

• Percentage of Participants With Overall Survival (OS) (Primary), Number, percentage of participants: Hematopoietic Stem Cell Transplant 80.4 (68.6 to 88.2)
• Percentage of Participants With Overall Survival (OS) by Disease Type (Secondary), Number, percentage of participants: Hemophagocytic Lymphohistiocytosis (HLH) 82.4 (68.4 to 90.6); Other Primary Immune Deficiencies (PID) 75.0 (47.4 to 89.5)
• Percentage of HLH Participants With HLH Reactivation Post-Transplant (Secondary), Number, percentage of participants: Hematopoietic Stem Cell Transplant 14.7 (5.2 to 28.7)
• Percentage of Participants With Neutrophil Engraftment (Secondary), Number, percentage of participants: Hematopoietic Stem Cell Transplant 100.0 (90.8 to 100.0)
• Percentage of Participants With Platelet Engraftment (Secondary), Number, percentage of participants: Hematopoietic Stem Cell Transplant 88.9 (73.3 to 95.6)
• Percentage of Participants Alive With Sustained Engraftment (Secondary), Number, percentage of participants: Hematopoietic Stem Cell Transplant 39.1 (25.1 to 54.6)
• Percentage of Participants Alive With Sustained Engraftment by Disease Type (Secondary), Number, percentage of participants: Hemophagocytic Lymphohistiocytosis (HLH) 41.2 (24.7 to 59.3); Other Primary Immune Deficiencies (PID) 33.3 (9.9 to 65.1)
• Number of Participants With Acute Graft-Versus-Host Disease (GVHD) (Secondary), Count of participants, Participants: Hematopoietic Stem Cell Transplant 35
• Percentage of Participants With Grade II-IV and Grade III-IV Acute GVHD (Secondary), Number, percentage of participants: Hematopoietic Stem Cell Transplant 17.4 (8.1 to 29.7)
• Number of Participants With Chronic GVHD (Secondary), Count of participants, Participants: Hematopoietic Stem Cell Transplant 34
• Percentage of Participants With Chronic GVHD (Secondary), Number, percentage of participants: Hematopoietic Stem Cell Transplant 26.7 (14.6 to 40.4)

Adverse events

Time frame: 1 year post-transplant

Serious adverse events by term

• Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8. PMID 7581076
• Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004. PMID 16338616
• Results publication: Geerlinks AV, Scull B, Krupski C, Fleischmann R, Pulsipher MA, Eapen M, Connelly JA, Bollard CM, Pai SY, Duncan CN, Kean LS, Baker KS, Burroughs LM, Andolina JR, Shenoy S, Roehrs P, Hanna R, Talano JA, Schultz KR, Stenger EO, Lin H, Zoref-Lorenz A, McClain KL, Jordan MB, Man TK, Allen CE, Marsh RA. Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT. Blood Adv. 2023 Jul 25;7(14):3725-3734. doi: 10.1182/bloodadvances.2022009478. PMID 37042921

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2015-06-16)

• Mary Horowitz, MD, MS, Study director, Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin

NIH grants: U10HL069294, U24CA076518