α1-antitrypsin (AAT) Levels and Functions in Allogeneic Bone Marrow Transplantation and Throughout Progression Into GVHD

Study Overview
=================
Brief Summary
-----------------
Create a personalized time and context curve of patient circulating α1-antitrypsin (AAT) levels and functions before hematopoietic stem cell transplantation and throughout progression into GVHD. PRIMARY ENDPOINT 1. Serum AAT levels and activity, before myeloablative preconditioning, as well as on days (-3),0,7,14,28 from HSCT and every 21 days thereafter. SECONDARY ENDPOINTS 1. Correlation between AAT patterns and: Circulating immune cell activation profiles on day of ablation, 28 days from HSCT and once GVHD is diagnosed. Patient survival Liver function tests GVHD grade: skin manifestations, weight, GI and liver histopathology Graft-versus-leukemia effect

Detailed Description
-----------------
This study will focus on each individual patient from the early point of myeloablative conditioning through HSCT and GVHD. The rationale for this individualized approach is to account for the anticipated variability in patient age and primary disease, background pathology and individual therapeutic course, considering the enormous heterogeneity of this condition. To compensate for this limitation, we intend to create an individualized algorithm, based on a novel dynamic biomarker, i.e., AAT functionality, individualized per patient and placed on a timeline, with the aim of minimizing future occurrences of GVHD, and by using readily available laboratory measurements. The study is designed around patient sample collection, there is no change in standard of care, therefore there is no intervention as well. Three types of sample tubes will be collected per indicated time point: Serum tube for protein levels and enzymatic activity assays. EDTA tube for isolation of peripheral blood mononuclear cells (PBMCs), cells will be stimulated and then analyzed by FACS and lysed for RT-PCR EDTA tube for whole blood stimulation assay for further FACS analysis and cytokine production measurement. After donor and recipient informed consent forms were signed, a single blood sample should be obtained from the donor on the day of transplant extraction. Time points for recipient's samples include the day of myeloablation and again immediately prior to HSCT (set as day 0 and possibly -3 in MUDs). Serum and lysed blood samples will be collected on days 7, 14, 28, and every 21 days thereafter, through the development and progression of GVHD (where relevant). Blood samples for FACS will be collected by days 0 and 28. Sample collection is planned to end within 1 year from HSCT, or two months after appearance of symptoms of GVHD, or two months after a change is introduced in the immunosuppressive therapy.

Official Title
-----------------
Relative Inactivity of Alpha-1-antitrypsin After Bone Marrow Transplantation as a Dynamic Biomarker for GVHD and Prognosis: a Prospective Cohort Study

Conditions
-----------------
GVHD, Bone Marrow Transplant Failure, Alpha 1-Antitrypsin

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Candidates for allogeneic transplantation for the first time, scheduled to receive HSCT from HLA-matched sibling or an unrelated matched donor Signed informed consent by the donor(Healthy volunteers) and the patient Exclusion Criteria: Patients undergoing immunosuppressive treatment prior to preparation for bone-marrow transplantation. Pregnant and disabled patients.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Rambam<br>Approximately 40 patients in total.No intervention planned. | |
| Soroka<br>Approximately 10 patients in total.No intervention planned. | |
| Tel Aviv Souraski<br>Approximately 40 patients in total.No intervention planned. | |
| Jerusalem Hadassah<br>Approximately 50 patients in total. No intervention planned. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients progressing into acute or chronic GVHD | Evaluation of patient circulating alpha-1-antitrypsin levels and enzymatic functions as a bio-marker for GVHD progression and grading | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between AAT pattern and survivability, response to immunosuppressive treatment. liver functions, immunocyte activities. | Correlation between AAT patterns and: Circulating immune cell activation profiles on day of ablation, 28 days from HSCT and once GVHD is diagnosed. Patient survival Liver function tests GVHD grade: skin manifestations, weight, GI and liver histopathology Graft-versus-leukemia effect | Up to 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Trypsin Inhibitors, Graft vs Host Disease, Immune System Diseases, Protease Inhibitors, Alpha 1-Antitrypsin, Enzyme Inhibitors, Molecular Mechanisms of Pharmacological Action, Serine Proteinase Inhibitors