Trial Title:
The Endothelial Cell Dysfunction and Outcome Project for Hematological Neoplasms
NCT ID:
NCT05502887
Condition:
Hematological Neoplasm
Endothelial Dysfunction
Conditions: Official terms:
Neoplasms
Hematologic Neoplasms
Conditions: Keywords:
endothelial cells
biomarkers
endothelial activation and stress index (EASIX)
endothelial complications
non-relapse mortality
in vivo microscopy
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
Sublingual in vivo microscopy with the Glycocheck microscope
Description:
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.
Arm group label:
Researched Group
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.
Detailed 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.
Criteria for eligibility:
Study pop:
All patients with newly diagnosed or preexistent hematological neoplasms at participating
centers are intended to be registered within EndoCDO-H. Prior to inclusion, patients have
to give their written informed consent.
Sampling method:
Non-Probability Sample
Criteria:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Department of Internal Medicine V, Heidelberg University Hospital
Address:
City:
Heidelberg
Zip:
69120
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Thomas Luft, MD
Phone:
+49 6221 568001
Email:
thomas.luft@med.uni-heidelberg.de
Contact backup:
Last name:
Richard F Schlenk, MD
Phone:
+49 6221 566228
Email:
richard.schlenk@nct-heidelberg.de
Start date:
September 1, 2022
Completion date:
June 7, 2032
Lead sponsor:
Agency:
Prof. Dr. Thomas Luft
Agency class:
Other
Source:
University Hospital Heidelberg
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05502887