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

NCT ID: NCT01998633

Last Updated: 2022-12-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2016-12-31

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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hematopoietic Stem Cell Transplant

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

Group Type: EXPERIMENTAL

Hematopoietic Stem Cell Transplant

Intervention Type: 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)

Interventions

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)

Intervention Type: BIOLOGICAL

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.

• Minimum Eligible Age: 4 Months
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD, MS

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Johns Hopkins

Baltimore, Maryland, United States

Dana Farber Cancer Institute/Children's Hospital of Boston

Boston, Massachusetts, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

Washington University/St. Louis Children's Hospital

St Louis, Missouri, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, 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

Duke University Medical Center

Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Medical Center of Dallas

Dallas, Texas, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Midwest Children's Cancer

Milwaukee, Wisconsin, United States

British Columbia Children's Hosp-Vancouver

Vancouver, British Columbia, Canada

Hopital Sainte-Justine

Montreal, Quebec, Canada

McGill University - Montreal

Montreal, Quebec, Canada

Countries

United States; Canada

References

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.

Reference Type: BACKGROUND

PMID: 7581076 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16338616 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37042921 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

2U10HL069294-11

Identifier Type: NIH

Identifier Source: secondary_id

View Link

5U24CA076518

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMTCTN1204

Identifier Type: -

Identifier Source: org_study_id