Hemophagocytic LymphohistiocytosisPhase 2RICHINCT01998633
Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
A Phase 2 study testing Hematopoietic Stem Cell Transplant in people with Hemophagocytic Lymphohistiocytosis and Chronic Active Epstein-Barr Virus Infection, run by Medical College of Wisconsin at 22 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 4 months to 45 years
- Conditions the study is for
- Hemophagocytic Lymphohistiocytosis, Chronic Active Epstein-Barr Virus Infection, Chronic Granulomatous Disease
- What is being tested?
- Hematopoietic Stem Cell Transplant
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 47 participants
- Where
- 22 sitesin 2 countries
- Study dates
- Dec 2013to Dec 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 months to 45 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patient is ≥ 3 months and ≤ 45 years of age at time of enrollment.
- 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]
Show all 17Show fewer
- 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:
- 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:
- Cardiac: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction (LVSF) > 26% by echocardiogram.
- Renal: Calculated or radioisotope Glomerular Filtration Rate (GFR) > 50 mL/min/1.73m^2
- 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).
- 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.
Who cannot join
- Hematopoietic stem cell transplant within 6 months of enrollment.
- 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).
- Pregnant or breastfeeding.
- Seropositive for human immunodeficiency virus (HIV).
- Alemtuzumab within 2 weeks of enrollment.
- 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.
Trial locations and contacts
22 sites in 2 countries.
22 sites in 2 countries
United States19 sites
University of Michigan Medical Center
Ann Arbor, Michigan, 48105-2967
Children's Healthcare of Atlanta
Atlanta, Georgia, 30322
Johns Hopkins
Baltimore, Maryland, 21231
University of Alabama at Birmingham
Birmingham, Alabama, 35294
Dana Farber Cancer Institute/Children's Hospital of Boston
Boston, Massachusetts, 02215
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599-7305
Ann and Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, 60614-3363
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229-3039
Children's Medical Center of Dallas
Dallas, Texas, 75235
Duke University Medical Center
Durham, North Carolina, 27705
Cook Children's Medical Center
Fort Worth, Texas, 76104
Baylor College of Medicine
Houston, Texas, 77030
Midwest Children's Cancer
Milwaukee, Wisconsin, 53211
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
Oregon Health and Science University
Portland, Oregon, 97239-3098
University of Rochester Medical Center
Rochester, New York, 14642
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109-1024
Washington University/St. Louis Children's Hospital
St Louis, Missouri, 63110
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Canada3 sites
Hopital Sainte-Justine
Montreal, Quebec, H3T1C5
McGill University - Montreal
Montreal, Quebec, H4A 3J1
British Columbia Children's Hosp-Vancouver
Vancouver, British Columbia, V5Z 4E3
About this study
Official title: Reduced-Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (RICHI) (BMT CTN #1204)
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.
Read the 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.
- Conditions
- Hemophagocytic Lymphohistiocytosis, Chronic Active Epstein-Barr Virus Infection, Chronic Granulomatous Disease, HIGM-1, Leukocyte Adhesion Deficiency, IPEX
- Being tested
- Hematopoietic Stem Cell Transplant
- 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)
- Medical subject headings
- Lymphohistiocytosis, Hemophagocytic, Granulomatous Disease, Chronic, Hyper-IgM Immunodeficiency Syndrome, Leukocyte adhesion deficiency type 1
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hematopoietic Stem Cell TransplantBiological
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)
| Study group | Role | What they receive |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Experimental | Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant. Receives: Biological: Hematopoietic Stem Cell Transplant |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants With Overall Survival (OS)
Overall survival is defined as survival of death from any cause.
Measured: 1 year and 18 months post-transplant
Secondary outcomes (10)
Percentage of Participants With Overall Survival (OS) by Disease Type
Overall survival is defined as survival of death from any cause.
Measured: 1 year and 18 months post-transplant
Percentage of HLH Participants With HLH Reactivation 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.
Measured: 1 year post-transplant
Percentage of Participants With Neutrophil Engraftment
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.
Measured: Day 42 post-transplant
Percentage of Participants With Platelet Engraftment
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.
Measured: Day 100 post-transplant
Percentage of Participants Alive With Sustained Engraftment
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.
Measured: 1 year post-transplant
Percentage of Participants Alive With Sustained Engraftment by Disease Type
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.
Measured: 1 year post-transplant
Number of Participants With Acute Graft-Versus-Host Disease (GVHD)
Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:
Skin stage:
0: No rash
- Rash <25% of body surface area
- Rash on 25-50% of body surface area
- Rash on > 50% of body surface area
- Generalized erythroderma with bullous formation
Liver stage (based on bilirubin level)*:
0: <2 mg/dL
- 2-3 mg/dL
- 3.01-6 mg/dL
- 6.01-15.0 mg/dL
- >15 mg/dL
GI stage*:
0: No diarrhea or diarrhea <500 mL/day
- Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD
- Diarrhea 1000-1499 mL/day
- Diarrhea >1500 mL/day
- 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
Measured: 1 year post-transplant
Percentage of Participants With Grade II-IV and Grade III-IV Acute GVHD
Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:
Skin stage:
0: No rash
- Rash <25% of body surface area
- Rash on 25-50% of body surface area
- Rash on > 50% of body surface area
- Generalized erythroderma with bullous formation
Liver stage (based on bilirubin level)*:
0: <2 mg/dL
- 2-3 mg/dL
- 3.01-6 mg/dL
- 6.01-15.0 mg/dL
- >15 mg/dL
GI stage*:
0: No diarrhea or diarrhea <500 mL/day
- Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD
- Diarrhea 1000-1499 mL/day
- Diarrhea >1500 mL/day
- 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
Measured: Day 100 and 6 months post-transplant
Number of Participants With Chronic GVHD
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.
Measured: 1 year post-transplant
Percentage of Participants With Chronic GVHD
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.
Measured: 1 year post-transplant
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2013 (estimated)
- Study startDec 2013
- Primary completion23 Sep 2016
- Study completionDec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Hemophagocytic LymphohistiocytosisStudies of the same condition, open and under way.
- More trials run by Medical College of WisconsinThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical College of Wisconsin
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Marrow Donor Program
- Responsible party
- Sponsor
- Investigators
- Mary Horowitz, MD, MS, Study director, Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01998633
- Sponsor's protocol ID
- BMTCTN1204
- Other IDs
- 2U10HL069294-11, 5U24CA076518
- Acronym
- RICHI
- Status last verified
- Dec 2022
- First submitted
- 29 Oct 2013
- Last updated
- 8 Dec 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Findings will be published in a manuscript.
Publications
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.
PubMed 7581076Filipovich 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.
PubMed 16338616Geerlinks 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.
PubMed 37042921
Study at a glance
From the registry record, last updated by the sponsor on 8 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reduced-Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (RICHI) (BMT CTN #1204)
- ClinicalTrials.gov ID
- NCT01998633
- Acronym / sponsor ID
- RICHI / BMTCTN1204
- Conditions
- Hemophagocytic Lymphohistiocytosis, Chronic Active Epstein-Barr Virus Infection, Chronic Granulomatous Disease, HIGM-1, Leukocyte Adhesion Deficiency, IPEX
- 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)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 47 participants (actual)
- Lead sponsor
- Medical College of WisconsinUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Marrow Donor Program
- Study start
- Dec 2013 (actual)
- Primary completion
- 23 Sep 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 2 Dec 2013 (estimated)
- Results
- Posted 1 Jun 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Hematopoietic Stem Cell Transplant | Experimental | Biological: Hematopoietic Stem Cell TransplantParticipants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant. |
Who may qualify
- Ages
- 4 months to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (17 listed)
- Patient is ≥ 3 months and ≤ 45 years of age at time of enrollment.
- 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]
Key exclusion criteria (6 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Hematopoietic Stem Cell TransplantNOTE: 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) | Biological | Hematopoietic Stem Cell Transplant |
Primary outcome
Percentage of Participants With Overall Survival (OS)
Time frame: 1 year and 18 months post-transplant
Overall survival is defined as survival of death from any cause.
10 secondary outcomes
Percentage of Participants With Overall Survival (OS) by Disease Type
Time frame: 1 year and 18 months post-transplant
Percentage of HLH Participants With HLH Reactivation Post-Transplant
Time frame: 1 year post-transplant
Percentage of Participants With Neutrophil Engraftment
Time frame: Day 42 post-transplant
Percentage of Participants With Platelet Engraftment
Time frame: Day 100 post-transplant
Percentage of Participants Alive With Sustained Engraftment
Time frame: 1 year post-transplant
Percentage of Participants Alive With Sustained Engraftment by Disease Type
Time frame: 1 year post-transplant
Number of Participants With Acute Graft-Versus-Host Disease (GVHD)
Time frame: 1 year post-transplant
Percentage of Participants With Grade II-IV and Grade III-IV Acute GVHD
Time frame: Day 100 and 6 months post-transplant
Number of Participants With Chronic GVHD
Time frame: 1 year post-transplant
Percentage of Participants With Chronic GVHD
Time frame: 1 year post-transplant
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Dec 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 7581076Przepiorka 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.
- Background: PubMed 16338616Filipovich 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.
- Derived from this study: PubMed 37042921Geerlinks 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.
- Individual participant dataSharing planned: Yes. Findings will be published in a manuscript.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mary Horowitz, MD, MS study director
Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin
22 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Hematopoietic Stem Cell Transplant in people with Hemophagocytic Lymphohistiocytosis and Chronic Active Epstein-Barr Virus Infection, run by Medical College of Wisconsin at 22 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Jun 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Overall Survival (OS) (time frame: 1 year and 18 months post-transplant). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01998633, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Dec 2022.