Gut Decontamination In Pediatric Allogeneic Hematopoietic

Study Overview
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Brief Summary
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This research study is for participants who are undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and are at risk for developing acute graft-versus-host disease (GVHD). GVHD is a complication of HSCT in which immune cells from the donor cause inflammation and injury to tissues and organs of the HSCT recipient. Vancomycin-polymyxin B (commonly called vancopoly) is an oral antibiotic that is given to people undergoing allogeneic HSCT as a preventive measure for acute GVHD. This research study is studying the effects of vancopoly on the microorganisms living in the intestine during and after stem cell transplantation.

Detailed Description
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This research study is a Phase 2 clinical trial. Phase 2 clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. Pre-clinical studies performed in the 1970's showed that killing all the bacteria in the intestine with oral antibiotics could decrease the risk of acute GVHD following allogeneic HSCT. Based on this observation, many stem cell transplant centers adopted the practice of gut decontamination with oral antibiotics as a preventive measure for acute GVHD. There is no standard regimen for gut decontamination between transplant centers, and there are no definitive human studies showing that gut decontamination is beneficial for lowering the risk of acute GVHD. Recent studies in adult patients undergoing stem cell transplant indicate that the types of bacteria living in the intestine can influence bone marrow transplant outcomes such as survival and development of acute GVHD. Some types of bacteria may be protective against GVHD and others may increase the risk of GVHD. Based on this newer research, it is possible that the practice of gut decontamination (vancopolys) may not be beneficial for HSCT patients.

Official Title
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A Randomized Phase 2 Study to Examine the Impact of Gut Decontamination on Intestinal Microbiome Composition in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Patients

Conditions
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Hematopoietic Stem Cell Transplantation (HSCT), Acute GVH Disease

Intervention / Treatment
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* Drug: Vancomycin-polymyxin B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligibility Criteria for Patients Undergoing Allogeneic HSCT Recipient of 9/10 or 10/10 (HLA-A, -B, -C, -DRB1, -DQB1) matched bone marrow allogeneic hematopoietic stem cell transplantation (HSCT) OR 4/6, 5/6 and 6/6 (HLA-A, -B, -DR) matched cord blood allogeneic HSCT. Participants may have underlying malignant or non-malignant hematologic disease, except for primary immunodeficiency, as the indication for their allogeneic HSCT. Patients with immune dysregulation such as familial or secondary hemophagocytic lymphohistiocytosis (HLH) are eligible. Participants must may receive either a myeloablative or non-myeloablative(reduced-intensity) conditioning regimen. Anti-thymocyte globulin (ATG) in the conditioning regimen is permitted. Graft-versus-host disease (GVHD) prophylaxis with any of the following agents: calcineurin inhibitor, and short-course methotrexate, with or without steroids, mycophenolate mofetil, and sirolimus. Age ≥ 4 years old and toilet-trained. Participants must be able to deposit stool samples directly into stool collection containers. Stool specimens from diapers are difficult to obtain and are prone to more sampling error, particularly for loose or liquid stools which are common in the peri-transplant period. Lansky/Karnofsky performance status ≥60% (see Appendix A) Ability to understand and/or the willingness of their parent or legally authorized representative to sign a written informed consent document Eligibility Criteria for Healthy Bone Marrow Donors Healthy individuals, ages ≥ 4 years and toilet-trained, who have been identified by BCH or DFCI providers as 9/10 or 10/10 (HLA-A, -B, -C, -DRB1, -DQB1 matched bone marrow donors for transplantation will also be eligible to participate in this study. Exclusion Criteria: Patients undergoing allogeneic HSCT for correction of a primary immunodeficiency disorder (e.g. SCID). Patients with age ≤ 10 years undergoing HSCT with a matched sibling donor. These patients are at very low risk of acute GVHD and do not receive gut decontamination per our institutional standard practice. Participants receiving GVHD prophylaxis with drugs other than calcineurin inhibitors, methotrexate or steroids.agents listed above (e.g. abatacept). History of allergic reactions attributed to oral vancomycin or oral polymyxin B. Participants undergoing active therapy for immune-mediated or infectious colitis upon admission for allogeneic HSCT. Participants receiving antibiotic therapy for treatment of a bacterial infection or bacterial prophylaxis upon admission for allogeneic HSCT. Use of any agent (e.g. sulfamethoxazole/trimethoprim) for prophylaxis of Pneumocystis jirovecii pneumonia is permitted. Concurrent use of anti-fungal and anti-viral therapies is also permitted. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gut Decontamination with vancopoly<br>All eligible participants will be randomized to either Arm A: Gut Decontamination or Arm B: No Gut Decontamination. Participants assigned to this arm will receive non-absorbable, oral vancomycin-polymyxin B as per our institutional standard practice. | Drug: Vancomycin-polymyxin B<br> <br> |
| No Intervention: No Gut Decontamination<br>All eligible participants will be randomized to either Arm A: Gut Decontamination or Arm B: No Gut Decontamination. Participants assigned to this arm will not receive oral vancomycin-polymyxin B, but all other HSCT supportive care will be the same as for patients in Arm A. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut Microbiome Description | Shannon diversity index (range: 0-6), measured at 2 weeks post stem cell transplant. Shannon diversity is a way to calculate biodiversity in a community, and assumes that all species are represented in a sample and that they are randomly sampled. Shannon Diversity is a measurement sensitive to the loss of rare taxa (34 in the JCI Insight manuscript, Konopinski MK, PeerJ. 2020;8:e9391) and estimates microbial richness (e.g., the number of species) and evenness (e.g., the relative abundance of organisms within a sample). Formula 1: H = -∑[(pi) * ln(pi)], H: Shannon diversity index (H = 0 indicates that a community has only one species) pi: Proportion of individuals of i-th species in a whole community Formula 2: pi = n / N, n: individuals of a given type/species N: total number of individuals in a community | 2 Weeks post HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diarrhea Frequency | The number of daily bowel movements during the first 7 days post-HSCT is charted by floor nurses and/or clinical assistants and will be obtained from within each patient's electronic medical record in PowerChart. Diarrhea frequency is defined the proportion of participants who had greater than 3 bowel movements per day. | Participants were followed 7 days after HSCT. | 
| Median Absolute Cell Numbers of T-, B-, NK- and Dendritic Cell Subsets by Flow Cytometry | CD4+ Tregs were defined as CD3+CD4+CD25med-hiCD127lo, CD4+; Tcon as CD3+CD4+CD25neg-lo CD127med-hi, B cells as CD19+, cytotoxic T cells as CD8+, and natural killer cells as CD56+CD3-. Within CD4+ Tregs and CD4+ Tcon, subsets were defined as follows: naive T cells (CD45RO-CD62L+), central memory (CD45RO+CD62L+), and effector memory (CD45RO+CD62L-). | Performed at the post-transplant time points (1,2,3,6,9,12 months post-transplant) | 
| Incidence of Acute GVHD (Grade 2-4) | Grade 2 acute GVHD was defined as skin stage 3 or GI stage 1 or liver stage 1. Skin stage 3 was defined as maculopapular rash >50% of body surface or generalized erythroderma; GI stage 1 was defined as adults: 500 - 1000 mL/day, children: 10 - 19.9 mL/kg/day or nausea, anorexia or vomiting with biopsy (EGD) confirmation of upper GI GVHD; liver stage 1 was defined as bilirubin 2.1-3 mg/dL. Grade 3 acute GVHD was defined as GI stage 2-4 or liver stage 2-3. GI stage 2-4 was defined as >1001 mL/day (adults), >30 ml/kg/day(children) or large volume stool with severe abdominal pain with our whiteout ileus or stool with frank blook or melena; liver stage 2-3 was defined as bilirubin 3.1-15mg/dL. Grade 4 acute GVHD was defined as skin stage 4 or liver stage 4. Skin stage 4 was defined as generalized erythroderma with bullous formation and desquamation; liver stage 4 was defined as bilirubin > 15mg/dL. | Each stool collection time point after neutrophil engraftment until day +100 | 
| Overall Survival Rate at 12 Months (OS12) | OS12 is the proportion of participants alive at 12 months after study entry. | All participants were followed for 1 years after study entry. | 
| Relapse Free Rate at 12 Months | Relapse free rate at 12 months was defined as the proportion of patients surviving without any signs or symptoms of that cancer after 12 months. | Patients were followed for 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematopoietic Stem Cell Transplantation (HSCT), Acute GVH Disease