The Endothelial Cell Dysfunction and Outcome Project for Hematological Neoplasms

Endothelial Dysfunction Clinical Trial

— EndoCDO-H  

Official title:

The Endothelial Cell Dysfunction and Outcome Project for Hematological Neoplasms (EndoCDO-H). A Prospective Registry Study on Endothelial Functional Profile, Intervention Type and Clinical Outcome in Patients With Hematological Neoplasms

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05502887
• Other study ID #: EndoCDO-H
• Status: Recruiting
• Start date: September 1, 2022
• Est. completion date: June 7, 2032

Study information

• Verified date: May 2024
• Source: University Hospital Heidelberg
• Contact: Prof. Dr. Thomas Luft
• Phone: +49 06221/56 8030
• Email: Thomas.Luft[@]med.uni-heidelbe
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The endothelium is a semipermeable monolayer of endothelial cells (EC) organized as a complex biological interface that separates all tissues from circulating blood. Any anti-neoplastic or immune therapy will directly challenge the endothelial layer, with a substantial risk of damaging EC or exacerbating pre-existing endothelial cell dysfunction.

In our previous researchs the concepts of "endothelial vulnerability" and "endothelial cell dysfunction" for initial diagnosis of patients with hematological disorders, e.g. myelodysplastic syndromes as well as COVID-19 patients were designed. The novel and pre-existing endothelial vulnerability markers and markers of endothelial cell dysfunction or damage such as endothelial activation and stress index (EASIX) were also defined, validated and their prognostic role for treatment-related mortality and for a variety of allo- and CART-specific endothelial complications were established. However, the exact relationship of EASIX and other markers with endothelial cell biology are not known and require further clarification.

Primary aims are to demonstrate that EASIX represents a systemic response of the organism to local or systemic loss of endothelial glycocalyx as visualized by sublingual microscopy and to establish EASIX, biomarkers and in vivo microscopy of sublingual and (in perspective) recto-sigmoidal capillary beds as prognostic markers of response to anti-neoplastic therapy, treatment-related toxicity and mortality (TRM) and overall survival (OS). Secondary objectives include the creation of a comprehensive database with information on endothelial, clinical, pathological and molecular characteristics of patients with hematological malignancies as well as the establishment of a repository of biospecimens for endothelial marker analyses from patients with hematological malignancies.

We hypothesize that reduced endothelial glycocalyx thickness will permit direct interactions of leukocytes and platelets with endothelial cells, resulting in cellular activation (increased LDH), loss of platelets due to activation and microembolism, and ensuing kidney damage. As a first prospective analysis, we will answer the question if EASIX and serum endothelial biomarkers correlate with sublingual glycocalyx thickness, and if these parameters combine to predict outcome after anti-neoplastic therapy including alloSCT and CART.

Description:

Functional heterogeneity is a hallmark of the endothelial cell system. The hypothetical functional definition of ECs as input-output devices emphasizes their role as direct responders to a variety of challenges such as blood pressure, temperature, pH and oxygen pressure, and serum factors. Maintaining homeostasis of tissue perfusion is an important function of ECs that are continuously exposed to stimuli provided by the alternative complement pathway, coagulation factors, cytokines, activated platelets, leukocytes, and occasional infectious agents. Due to their distribution over space and time, hardly two ECs will be exposed to the same set of input signals 8. Moreover, stochastic or inheritable heterogeneous DNA methylation patterns add to the functional variability of seemingly "homogeneous" mature EC populations. Therefore, tissue-specific stress responses of ECs can explain that even during systemic EC dysfunction (e.g. due to calcineurin inhibitors, viruses, TBI etc.), microangiopathy develops locally in individual patients. This functional heterogeneity has to be considered in all attempts to define clinical diagnostic criteria for endothelial complications after hematological anti-neoplastic therapy including alloSCT and CART infusions.

Over the last years, our group has developed the concepts of "endothelial vulnerability" and "endothelial cell dysfunction" that pre-exist before alloSCT and CART infusions and at initial diagnosis of patients with hematological disorders, e.g. myelodysplastic syndromes, but also in COVID-19 patients. We have defined and validated novel and pre-existing endothelial vulnerability markers (e.g. single nucleotide polymorphisms in THBD (Thrombomodulin) and CD40 Ligand; serum levels of Angiopoietin-2, serum nitrates, asymmetric dimethyl-arginine (ADMA), testosterone deficiency, interleukin-18), and markers of endothelial cell dysfunction or damage (e.g. suppressor of tumorigenicity (ST)-2, interleukin-18, insulin-like growth factor 1 (IGF1), CXCL8), and we have established their role as prognostic markers for treatment-related mortality and for a variety of allo- and CART-specific endothelial complications.

The heterogeneity of EC explains why global one-for-all markers were not found within the group of endothelial-derived and endothelial-specific prognostic factors. We therefore developed the Endothelial activation and stress index, EASIX, as a marker that represents the response of the organism to endothelial dysfunction. EASIX represents an interplay of the basic laboratory parameters (LDH*creatinine/platelets) observed at onset of the most severe endothelial complication after alloSCT, i.e. transplant-associated thrombotic microangiopathy (TAM). EASIX correlated with endothelial serum markers such as IL18, ANG2 and IGF1 and predicted outcome in a variety of clinical settings including COVID-19. However, the exact relationship of EASIX to endothelial cell biology requires further clarification. We hypothesize that reduced endothelial glycocalyx thickness will permit direct interactions of leukocytes and platelets with endothelial cells, resulting in cellular activation (increased LDH), loss of platelets due to activation and microembolism, and ensuing kidney damage.

Thus, key areas of interest are:

• Comprehensive collection and intercorrelation of endothelial parameters before, during and after new lines of therapy including in vivo microscopy, ECHO cardiography, EASIX, body weight, endothelial serum markers including, but not restricted to, ST2, ANG2, IL18, IL8, sCD141, Hyaluronan, Syndecan-1, CXCL9, Leptin, Adiponectin, Testosterone, and others.

• Correlation of EASIX with glycocalyx thickness and capillary flow measured by in vivo microscopy of the capillary bed.

• Systematic collection of clinical data on known endothelial complications, including, but not restricted to, sepsis, septic shock, macrophage activation syndrome, veno-occlusive disease / sinusoidal obstruction syndrome (SOS/VOD), thrombotic microangiopathy, idiopathic pneumonia syndromes (IPS), paraneoplastic syndromes, engraftment syndrome, persistent intestinal inflammation, cachexia, and others.

• Systematic collection and evaluation of comprehensive biological specimens and information from patients with hematological neoplasms, including data on the genomic, transcriptomic, epigenomic and proteomic "landscapes" as well as expression of surface antigens of hematological disease subtypes, to identify novel prognostic and predictive endothelial parameters as well as entry points for targeted therapeutic interventions that protect the endothelium.

• Multivariable prediction analyses of endothelial parameters on outcome and endothelial complications.

The above challenges are ideally met by a registry study with a sufficient population size to answer relevant questions in rare therapy-related complications and rare cancer entities.

The aim is to set up a registry study that covers systematic and comprehensive clinical data acquisition, and longitudinal banking of serum, blood cells and bone marrow samples of patients with hematological diseases, with focus on in vivo microscopy, EASIX, and serum endothelial markers.

This resource will spur patient-oriented investigations into relationships between endothelial, clinical and tumor-biological parameters in hematological neoplasms and lay the groundwork for novel, supportive treatment approaches protecting the endothelial system in poorly understood and difficult-to-treat subsets.

As a first prospective analysis, we will answer the question if EASIX and serum endothelial biomarkers correlate with sublingual glycocalyx thickness, and if these parameters combine to predict outcome after anti-neoplastic therapy including alloSCT and CART.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1000
• Est. completion date: June 7, 2032
• Est. primary completion date: June 7, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Suspected or proven diagnosis of hematological neoplasms according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues;

• Age =18 years;

• Ability to understand nature and individual consequences of the registry;

• Written informed consent;

• Subjects who are physically or mentally capable of giving consen.

Exclusion Criteria:

• Severe neurological or psychiatric disorder interfering with the ability to give written informed consent.

Related Conditions & MeSH terms

• Endothelial Dysfunction
• Hematologic Neoplasms
• Hematological Neoplasm
• Neoplasms

Intervention

Diagnostic Test:
• Sublingual in vivo microscopy with the Glycocheck microscope
For the collection of longitudinal microscopy data, sublingual in vivo microscopy with the Glycocheck microscope will be performed at the following timepoints: 2-3 x between day (D) -28 of allogeneic HSCT or CAR T cell therapy and before start of the conditioning regimen, once between D2-D14, once between D15-28, once between D30- D100 and at the onset of endothelial complications such as acute GvHD, TMA, sepsis, VOD and IPS following allogeneic HSCT or CAR T cell therapy. Sublingual microscopy requires 15-30 minutes and is similar to sublingual temperature measurement. To this extent, a tube with a diameter of approximately 1cm carrying a microscope at the tip is inserted into the mouth and under the tongue to measure endothelial structures (blood flow through small capillaries). Biological samples are collected and processed within the established Biobank of the Internal Medicine V of the Heidelberg University Hospital.

Locations

Country	Name	City	State
Germany	Department of Internal Medicine V, Heidelberg University Hospital	Heidelberg	Baden-Württemberg

Sponsors (1)

Lead Sponsor	Collaborator
Prof. Dr. Thomas Luft

Country where clinical trial is conducted

Germany, 

References & Publications (4)

Luft T, Benner A, Jodele S, Dandoy CE, Storb R, Gooley T, Sandmaier BM, Becker N, Radujkovic A, Dreger P, Penack O. EASIX in patients with acute graft-versus-host disease: a retrospective cohort analysis. Lancet Haematol. 2017 Sep;4(9):e414-e423. doi: 10.1016/S2352-3026(17)30108-4. Epub 2017 Jul 18. — View Citation

Luft T, Benner A, Terzer T, Jodele S, Dandoy CE, Storb R, Kordelas L, Beelen D, Gooley T, Sandmaier BM, Sorror M, Zeisbrich M, Radujkovic A, Dreger P, Penack O. EASIX and mortality after allogeneic stem cell transplantation. Bone Marrow Transplant. 2020 Mar;55(3):553-561. doi: 10.1038/s41409-019-0703-1. Epub 2019 Sep 26. — View Citation

Luft T, Dreger P, Radujkovic A. Endothelial cell dysfunction: a key determinant for the outcome of allogeneic stem cell transplantation. Bone Marrow Transplant. 2021 Oct;56(10):2326-2335. doi: 10.1038/s41409-021-01390-y. Epub 2021 Jul 12. — View Citation

Luft T, Wendtner CM, Kosely F, Radujkovic A, Benner A, Korell F, Kihm L, Bauer MF, Dreger P, Merle U. EASIX for Prediction of Outcome in Hospitalized SARS-CoV-2 Infected Patients. Front Immunol. 2021 Jun 23;12:634416. doi: 10.3389/fimmu.2021.634416. eCollection 2021. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	overall survival	Time period between date of informed consent to alive at last follow-up or death	observation peroid 10 years
Secondary	side effects	toxicity measured according to CTC AE version 5.0	observation peroid 10 years
Secondary	Treatment adaptation	reduction of dose intensity	observation peroid 10 years
Secondary	endothelial glycocalyx	endothelial glycocalyx measured by sublingual microscopy	observation peroid 10 years