Cell Free DNA Profiling As a Tool to Monitor Clinically-Relevant Events in Allogeneic Hematopoietic Stem Cell Transplantation

Overview

Allogeneic hematopoietic stem cell transplantation (HSCT) is a life-saving treatment for people with severe blood-related diseases. However, it comes with serious risks, including a condition called graft-versus-host disease (GVHD), where the transplanted cells attack the patient's body. GVHD can occur in about 50% of patients acutely and 35% in a chronic form, potentially affecting organs like the skin, liver, and gastrointestinal system. Currently, doctors diagnose GVHD based on symptoms, as there are no easy tests available. Infections can also be a problem after HSCT, as dormant viruses may reactivate. These infections are monitored using specialized tests. Additionally, doctors use advanced methods, like analyzing minimal residual disease (MRD) and chimerism, to check for the risk of the original disease coming back. MRD is tracked by looking for specific genetic markers of the disease in the patient's blood or bone marrow. Another emerging tool involves analyzing cell-free DNA (cfDNA)-tiny fragments of DNA found in bodily fluids that come from dying cells. This technique, called liquid biopsy, has been revolutionary in areas like cancer detection, pregnancy testing, and organ transplants. For example, in organ transplants, cfDNA can indicate early signs of rejection, helping reduce the need for invasive biopsies. In HSCT, the use of cfDNA to monitor complications like GVHD or relapse has not been fully explored. This pilot study aims to investigate whether analyzing cfDNA using a technique called epigenomic profiling can help detect acute GVHD, as well as other post-transplant issues like infections, disease relapse, and chronic GVHD. The goal is to compare cfDNA analysis to current testing methods to see if it offers better or earlier detection of complications. This research could pave the way for improved, less invasive monitoring of HSCT patients, potentially leading to better outcomes and fewer complications.

Interventions

• Diagnostic test Sample collation for cfDNA methylation analysis
  Sample collation for cfDNA methylation analysis
• Diagnostic test Sample collection for EV phenotype analysis
  Analysis of the EV phenotype to evaluate their potential value as markers for GVHD, relapse and engraftment.

Primary outcome measures

• Epigenetic profiling of cfDNA in patients developing GVHD [Time frame: From enrollment to the end of post-HSCT follow-up of 12 months]

Secondary outcome measures (5)

• Epigenetic profiling of cfDNA in patients developing post-HSCT infections [Time frame: From enrollment to the end of post-HSCT follow-up of 12 months]
• Epigenetic profiling of cfDNA in patients with engraftment failure [Time frame: From enrollment to the end of post-HSCT follow-up of 12 months]
• Epigenetic profiling of cfDNA in relapsing patients [Time frame: From enrollment to the end of post-HSCT follow-up of 12 months]
• Epigenetic profiling of cfDNA in patients developing transplant associated microangiopathy or sinusoidal obstruction [Time frame: From enrollment to the end of post-HSCT follow-up of 12 months]
• Evaluation of EV phenotype [Time frame: From enrollment to the end of post-HSCT follow-up of 12 months]

Eligibility criteria

Inclusion criteria

• Patient must be affected by an hematological malignancy requiring hematopoietic stem cell transplantation (HSCT).

Exclusion criteria

• Patients can not be 17 years old or yunger

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Italy · 2 centers

• Unità di Ematologia e Trapianto di Midollo Osseo e Oncoematologia of the San Raffaele Hosp — Milan
• SS Trapianto allogenico e terapie cellulari, SC Ematologia U of the Città della Salute e d — Turin

Publications

• Wang X, He B. Insight into endothelial cell-derived extracellular vesicles in cardiovascular disease: Molecular mechanisms and clinical implications. Pharmacol Res. 2024 Sep;207:107309. doi: 10.1016/j.phrs.2024.107309. Epub 2024 Jul 14. PMID 39009292
• Jodele S, Dandoy CE, Sabulski A, Koo J, Lane A, Myers KC, Wallace G, Chima RS, Teusink-Cross A, Hirsch R, Ryan TD, Benoit S, Davies SM. Transplantation-Associated Thrombotic Microangiopathy Risk Stratification: Is There a Window of Opportunity to Improve Outcomes? Transplant Cell Ther. 2022 Jul;28(7):392.e1-392.e9. doi: 10.1016/j.jtct.2022.04.019. Epub 2022 Apr 29. PMID 35490975
• Avni B, Neiman D, Shaked E, Gal-Rosenberg O, Grisariu S, Kuzli M, Avni I, Fracchia A, Stepensky P, Zuckerman T, Lev-Sagie A, Fox-Fisher I, Piyanzin S, Moss J, Salpeter SJ, Glaser B, Shemer R, Dor Y. Chronic graft-versus-host disease detected by tissue-specific cell-free DNA methylation biomarkers. J Clin Invest. 2024 Jan 16;134(2):e163541. doi: 10.1172/JCI163541. PMID 37971879
• Oellerich M, Budde K, Osmanodja B, Bornemann-Kolatzki K, Beck J, Schutz E, Walson PD. Donor-derived cell-free DNA as a diagnostic tool in transplantation. Front Genet. 2022 Oct 21;13:1031894. doi: 10.3389/fgene.2022.1031894. eCollection 2022. PMID 36339004
• Cheng AP, Cheng MP, Loy CJ, Lenz JS, Chen K, Smalling S, Burnham P, Timblin KM, Orejas JL, Silverman E, Polak P, Marty FM, Ritz J, De Vlaminck I. Cell-free DNA profiling informs all major complications of hematopoietic cell transplantation. Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2113476118. doi: 10.1073/pnas.2113476118. PMID 35058359

Identifiers

NCT: NCT06715046 · P2022ZRF5H

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗