We aim to quantify the contribution of individual HSCs to blood (re-)generation in pediatric HSCT recipients and their donors, and to unravel the consequences of transplantation on HSC long-term genomic integrity.
ID
Source
Brief title
Condition
- Anaemias nonhaemolytic and marrow depression
- Immunodeficiency syndromes
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Our main study endpoints are:
- The total number of somatic mutations acquired after HSCT in the HSCT
recipient and his/her donor;
- The frequency of HSC clones contributing to production of each of the mature
blood lineages in the HSCT recipient and donor.
- The impact of donor age on the number of HSC clones that contribute to
post-transplant hematopoiesis, and the genomic integrity of these cells
Secondary outcome
Secondary study outcomes are:
- Identification of potential causes of HSC mutagenesis upon HSCT, assessed by
mutational signature analysis
- Insight into the cellular and molecular pathways that guide HSC
(non-)engraftment
Background summary
Hematopoietic stem cell transplantation (HSCT) is a last-resort curative
therapy for patients suffering from various, otherwise lethal, diseases.
Despite the widespread use of HSCT in patients, the number of engrafting HSCs
and the mechanisms guiding their long-term contribution to hematopoiesis remain
elusive. Maintaining long-term HSC integrity is especially relevant in
children, who are now expected to survive for several decades after successful
HSCT. In the current project, we hypothesize that blood formation in human
allo-HSCT recipients is supported by a limited number of HSCs, and that the
proliferative stress posed upon these cells accelerates HSC mutagenesis,
ultimately predisposing to premature stem cell senescence and second
malignancy.
Study objective
We aim to quantify the contribution of individual HSCs to blood (re-)generation
in pediatric HSCT recipients and their donors, and to unravel the consequences
of transplantation on HSC long-term genomic integrity.
Study design
This is an observational, fundamental study. We will use an innovative
laboratory method, which employs single cell analysis of naturally occurring
genetic mutations to retrospectively reconstruct the number of HSCs clones,
their quantitative contributions to each of the mature blood lineages and their
mutational burden in human allo-HSCT recipients and their donors. The proposed
research involves collection of 10 mL venous blood of the HSCT recipient and
his/her donor.
Study burden and risks
This study requires pediatric recipients and their donors, as their
post-transplant survival exceeds that of adult HSCT recipients by several
decades, posing unique challenges on the integrity and longevity of the
engrafted HSCs. In addition, as clinical HSCT regimens differ between children
and adults (e.g. use of irradiation, chemotherapy dose), results obtained in
adult HSCT recipients cannot be translated directly to children,
We believe that the studies proposed here will provide unique insights into the
clonal behaviour and mutagenesis of transplanted human HSCs, which will
contribute to improved clinical HSCT protocols. In addition, knowledge on the
mechanisms that damage and/or protect HSC integrity may benefit our
understanding and treatment of blood diseases in general.
Heidelberglaan 25
Utrecht 3584CS
NL
Heidelberglaan 25
Utrecht 3584CS
NL
Listed location countries
Age
Inclusion criteria
Patients (n=30):
- Recipients of an allogeneic hematopoietic stem cell transplantation (HSCT)
from an umbilical cord blood donor (n=10), adult haplo donor (n=10), or healthy
sibling donor (n=10)
- Age at HSCT <18 yrs
- First HSCT
- >95% donor chimerism at the time of blood sampling
- Currently alive
- No major HSCT-related complications (see exclusion criteria),
Healthy subjects (n=20):
- Healthy donors of the sibling and haplo-HSCT recipients described above.
Exclusion criteria
- Major HSCT-related complications, such as >grade 2 graft versus host disease.
- Secondary graft failure
- Objection to be notified about actionable findings from whole-genome
sequencing.
- Failure of the HSCT recipient, donor and/or their legal representatives to
understand the patient information and informed consent form (either due to
intellectual disability or to language problems). Of note: For sibling and
haplo transplants, we will only include subjects in whom both the HSCT
recipient and his/her donor (and, if applicable, their caregivers) agree to
participate in the current study.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL68140.041.19 |
| Other | NL7585, Nederlands Trial Register |
| OMON | NL-OMON23273 |