Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
- Conditions
- Chronic Active Epstein-Barr Virus InfectionIPEXChronic Granulomatous DiseaseHemophagocytic LymphohistiocytosisHIGM-1Leukocyte Adhesion Deficiency
- Interventions
- Biological: Hematopoietic Stem Cell Transplant
- Registration Number
- NCT01998633
- Lead Sponsor
- Medical College of Wisconsin
- Brief 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 47
Not provided
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Hematopoietic Stem Cell Transplant Hematopoietic Stem Cell Transplant Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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 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.
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 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 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 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 4Percentage 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 4Number 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.
Trial Locations
- Locations (22)
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Ann and Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
University of Michigan Medical Center
🇺🇸Ann Arbor, Michigan, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
Washington University/St. Louis Children's Hospital
🇺🇸Saint Louis, Missouri, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Children's Medical Center of Dallas
🇺🇸Dallas, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Midwest Children's Cancer
🇺🇸Milwaukee, Wisconsin, United States
Hopital Sainte-Justine
🇨🇦Montreal, Quebec, Canada
McGill University - Montreal
🇨🇦Montreal, Quebec, Canada
Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Dana Farber Cancer Institute/Children's Hospital of Boston
🇺🇸Boston, Massachusetts, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
British Columbia Children's Hosp-Vancouver
🇨🇦Vancouver, British Columbia, Canada
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States