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

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

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

Study Overview

• Status: Completed
• Conditions: GVHD; Bone Marrow Transplant Failure; Alpha 1-Antitrypsin

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.

• Study Type: Observational
• Enrollment (Actual): 27

Contacts and Locations

Study Locations

• Israel
  • Center
    • Jerusalem, Center, Israel, 91120
      • Hadassah
    • Tel Aviv, Center, Israel, 6423906
      • Tel Aviv Sourasky Medical Center - Ichilov Hospital
  • North
    • Haifa, North, Israel, 3525408
      • Rambam MC
  • South
    • Beer sheva, South, Israel, 8410101
      • Soroka Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

In every medical center in which a bone marrow transplantation is performed, allogeneic transplantation recipients will be recruited for the trial.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Rambam; Approximately 40 patients in total.No intervention planned.
Soroka; Approximately 10 patients in total.No intervention planned.
Tel Aviv Souraski; Approximately 40 patients in total.No intervention planned.
Jerusalem Hadassah; 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

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Collaborators: Hadassah Medical Organization; Tel-Aviv Sourasky Medical Center; Soroka University Medical Center
• Investigators: Principal Investigator: Eli Lewis, Professor, Ben-Gurion University of the Negev

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2018
• Primary Completion (Actual): February 1, 2022
• Study Completion (Actual): August 1, 2022

Study Registration Dates

• First Submitted: June 13, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (Actual): June 15, 2017

Study Record Updates

• Last Update Posted (Actual): April 4, 2023
• Last Update Submitted That Met QC Criteria: April 2, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Immune System Diseases; Protease Inhibitors; Enzyme Inhibitors; Graft vs Host Disease; Molecular Mechanisms of Pharmacological Action; Serine Proteinase Inhibitors; Alpha 1-Antitrypsin; Trypsin Inhibitors
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Liver Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: 0196-17-RMB; A1373 (Other Grant/Funding Number: Rosetrees trust)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The clinical individual participant data will be further analyzed by other researchers after the study is completed.That is in order to combine this clinical data with other experiments' results. no

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No