Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04763148 |
| Other study ID # |
Heterogeneity in DLBCL |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 12, 2022 |
| Est. completion date |
March 1, 2023 |
Study information
| Verified date |
March 2023 |
| Source |
Herlev Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The aim of the project is to clarify whether DLBCL exhibits mutational diversity among
different lymph node tumors in one and the same patient. It is desired to find out whether a
possible difference between lymph node tumors / tumors can explain why patients who initially
(at diagnosis) have the same prognosis, sometimes have a completely different course, eg with
rapid recurrence of the disease after treatment.
A possible difference could also perhaps shed light on why disease in specific places spreads
more frequently to the brain - and therefore have an impact on when one chooses to give
preventive treatment against spread to the brain.
Monitoring of circulating cell-free DNA (ctDNA) is a new, potential, non-invasive tool for
measuring the full spectrum of genetic variations / mutations and is to be investigated in
our study as a possible non-invasive assessment of diversity / heterogeneity.
Description:
Only about 60% of patients with diffuse large B-cell lymphoma (DLBCL) are cured with standard
chemo- and immunotherapy, with R-CHOP(Rituximab, cyclophosphamide, doxorubicin hydrochloride,
oncovin, prednisone).
Early and more accurate identification of patients with unfavorable prognosis after R-CHOP
will enable the clinician to find patients who need other treatment strategies. New
predictive biomarkers are needed to predict the effect of treatment at the individual level.
A proportion of patients have, or develop, lymphoma involvement of the central nervous system
(CNS) and this group has a particularly dismal outcome. Identification of patients with
primary subclinical or later manifest involvement of the CNS also requires new and improved
diagnostic methods. Currently, a number of clinical parameters are included in a CNS-IPI risk
score, that can be used to predict the risk of CNS disease. This score enables the clinicians
to decide if patients should have prophylactic chemotherapy to prevent development of CNS
disease. However, this risk model is far from accurate and the effect of prophylactic
treatment is based on a low level of evidence.
DLBCL is a highly heterogeneous disease as evidenced by the 19 subtypes and variants of large
B-cell lymphoma diagnoses found in the WHO classification of tumors of hematopoietic and
lymphoid tissues. However, the cancer within each patient is also characterized by
heterogeneity. The fact that different lymphoma cells may co-exist in the same tumor has been
known for decades. One example of this is transformation of indolent lymphoma to a more
aggressive lymphoma subtype, often DLBCL where the two types of lymphoma cells are found in
the same lymph node. Differences between the cancer cells in the same tumor is termed
intratumor heterogeneity. Such differences may be found within the same tumor as well as at
spatially separate locations(inter-tumor heterogeneity). Intratumor heterogeneity may have an
important impact on the clinical course and response to therapy. In clinical practice, the
prognosis in patients with similar clinical stage and International Prognostic Index (IPI)
score is often diverse. Such differences may be attributed to both intra and inter-tumor
heterogeneity. Molecular profiling (mutations) in different nodal and extra nodal sites
within the same patient have not before been studied in larger cohorts of DLBCL patients
(Inter-tumor heterogeneity).
Monitoring circulating cell-free tumor DNA (ctDNA) has the potential to serve as a
non-invasive tool for measuring the entire spectrum of genetic aberrations found in an
individual patient as an alternative to more invasive diagnostic procedures.
Clinical presentation of DLBCL:
DLBCL is the most common type of lymphoma, and accounts for approximately 40% of non-Hodgkin
lymphomas in adults in Denmark (500 new cases per year). DLBCL can arise de novo or from the
histologic transformation of more indolent lymphomas, most commonly follicular lymphoma (FL)
and chronic lymphocytic leukemia (CLL). DLBCL primarily affects elderly patients with a
median age at diagnosis of nearly 70 years. Patients can present with both nodal and
extra-nodal involvement. More than one extra-nodal involvement is a negative prognostic
factor, and some sites are associated with higher risk of having or developing CNS
involvement (e.g. testis, adrenal glands, uterus).
DLBCL is characterized as a clinically heterogeneous disease with a variable outcome, however
it is potentially curable. R-CHOP is the standard therapy for patients with DLBCL. The 5-year
progression-free survival (PFS) is around 60%. However, more than 30% of patients treated
with R-CHOP do not respond or relapse, with the majority of these patients succumbing to
their disease. Despite risk models like the International Prognostic Index (IPI) and CNS-IPI,
patients with a high risk of treatment failure, relapse or CNS involvement cannot be
identified accurately by standard prognostic factors. Therefore, new prognostic factors and
biomarkers are under investigation at diagnosis, to better identify those high-risk patients,
who may benefit from an alternative therapeutic strategy.
Project aims and perspectives:
Our current understanding of the molecular mechanisms associated with DLBCL relapse is
limited. It is presently unclear whether clonal heterogeneity in primary tumors plays a role
in DLBCL relapse. Our study is based on the hypothesis that divergent subclones give rise to
the relapse tumor in an early-divergent scenario. This scenario suggest that several
divergent clones exist at diagnosis besides the one that gives rise to relapse. Thus,
information regarding intratumor heterogeneity and clonal evolution of the disease may
provide a better understanding of DLBCL and development of prognostic factors regarding
identification of high risk DLBCL patients. If the tumor is heterogenic, as studies of ctDNA
have indicated, it could potentially transform the clinical care paradigm. It could perhaps
explain the diverse outcome in patients with similarly clinical presentation, or why some
patients develop CNS involvement. Furthermore, knowledge of tumor heterogeneity could guide
the clinician in treatment choice and protocol development and thereby improve outcome for
the patients.
If heterogeneity could be detected in ctDNA it could be made operational and the patients
could avoid invasive biopsy procedures. The dynamic evolution of the tumor could perhaps also
be monitored by ctDNA regarding tumor burden related to interim and end of treatment PET-CT
and treatment intensity.
Current genomic models in DLBCL are mainly based on single tumor biopsies. They find a wide
spectrum of mutations between patients. The single tumor models may underestimate the
possible heterogeneity between tumor sites in the individual patient. Furthermore,
heterogeneity, data on mutational evolution and relationship with CNS involvement largely
remains unknown. Our setup will make it possible to clarify heterogeneity within the
individual patient and investigate the relation to prognosis and CNS involvement.
Primary objective of the study:
- To identify the pattern and variations of mutations in different lymphoma sites in
individual patients
Secondary objectives:
- To identify inter-tumor heterogeneity between nodal and extra nodal sites
- To identify the association between inter-tumor heterogeneity and risk of CNS
involvement
- To identify clonal evolution and clonal relationship between primary tumor site and
tumor at relapse
- To explore the role of "liquid biopsies" and ctDNA in monitoring inter-tumor
heterogeneity
- To identify heterogeneity between nodal sites and bone-marrow biopsy.
- Inter-patient heterogeneity identified with our local clinical lymphoma panel can be
used to subdivide patients according to the Wright classification
Clinical trials:
The project will consist of a retrospective study and an observational and clinical study.
5.1 Retrospective study - cohort A - Specific markers in patients with DLBCL
The first part of the retrospective study, cohort A, will be a study of different biopsies
taken from the same patient. The biopsies from different nodal and/or extra nodal sites have
either been taken at the same time or at different times in the treatment course. The time
period is 2015-2019.
The aim with cohort A is to explore the biopsy samples for various purposes:
- The biopsies taken at different times: give us the possibility to look at clonal
evolution over time.
- The biopsies, taken at the same time, but from different sites: gives us the possibility
to look at inter-tumor heterogeneity in one patient.
The results from different sites from the same patient will be compared and used to subgroup
the patient according to the Wright algorithm. All analyses will be performed on paraffin
embedded biopsy material.
Retrospective study - cohort B - Specific markers in patients with DLBCL and secondary CNS
involvement
In the retrospective study - cohort B, the investigators explore heterogeneity and clonal
evolution between CNS lymphoma and nodal/extra-nodal sites using already collected biopsies.
The investigators will look at patients with both systemic disease and involvement of the
central nervous system.
The time period is: 2010-2019
The aim with cohort B is to explore the biopsy samples for various purposes:
- The biopsies, taken from different sites (CNS vs systemic) gives us the possibility to
look at inter-tumor heterogeneity and possible clonal evolution.
- The biopsies taken at different times: give us the possibility to look at clonal
evolution over time
By comparing our results from the retrospective cohort A, the aim is to possibly define
particularly important mutations that are only present within patients whose disease has
spread to the central nervous system. Knowledge of mutations that may predispose to
involvement of the CNS would be essential in identifying patients with this risk.
The results from different sites from the same patient will be compared and used to subgroup
the patient according to the Wright algorithm. All analyses will be performed on paraffin
embedded biopsy material.
Prospective study - cohort A and B - Heterogeneity within lymphoma patients
The prospective study will include two different cohorts:
A: DLBCL patients with lymphoma involvement of several nodal sites accessible for biopsy and
bone-marrow.
B: DLBCL patients with both nodal, extra-nodal sites accessible for biopsy and bone-marrow.
The prospective study will include newly diagnosed patients with DLBCL. Patients will be
included in either cohort A or B according to localization of the disease ascertained by
PET-CT to clarify nodal vs extra-nodal involvement.
Cohort A - patients with more than one nodal site: One additional biopsy for clinical
evaluation will be performed from a different location than where the diagnostic biopsy was
performed. These biopsies can explore the heterogeneity within the patient at nodal sites.
Available bone-marrow biopsies will be analyzed as a separate site.
Cohort B - patients with both nodal and extra-nodal sites: One biopsy for clinical evaluation
will be performed from a different site than the diagnostic biopsy, resulting in one nodal
and one extra-nodal biopsy. These biopsies will explore the heterogeneity between nodal and
extra-nodal sites within the patient.
Any available bone-marrow biopsies will be analyzed as a separate site.
