The present study will be focused on defining the mechanisms that contribute to the increased vulnerability of HSPC for chemotherapy. In particular DNA damage response, ROS production and protective mechanism against stress response (NFR2) will be…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To obtain information regarding the increased vulnerability of HSPC for
chemotherapy, in vitro culture assays will be performed in the absence and
presence of cytostatic agents, in the presence and absence of mesenchymal cells
(MSC*s). The response of these cells will further be analyzed regarding the
induction of stress response (p53) and DNA damage response by performing gene
profiling and western blotting. In addition, the genetic and epigenetic
background of these cells will be analyzed and correlated with the obtained
results by performing targeted sequencing and Chip-seq. For these assays at
least 105 cells are required per experiment.
Secondary outcome
not applicable
Background summary
Autologous stem cell transplantation (ASCT) is an important treatment modality
for patients with lymphoma and myeloma. In lymphoma patients it is mostly
applied in relapsing disease following induction chemotherapy while in myeloma
patients it is part of the upfront treatment in chemotherapy sensitive disease.
In general, patients demonstrate a fast hematological recovery following high
dose chemotherapy and reinfusion of autologous stem cells. However, in 10%-15%
of the patients the recovery has a slower course, in particular regarding the
platelets. In addition, it has been shown that despite normal peripheral blood
cell counts following ASCT, the hematopoietic compartment is in general
affected by the applied transplantation procedure. This is reflected by an
increased susceptibility to chemotherapy resulting in prolonged pancytopenia in
10%-20% of the patients. In addition, an increased incidence of myelodysplasia
and acute myeloid leukemia has been demonstrated 3-6 years following ASCT, in
general with an unfavorable prognosis. Apparently the hematopoietic compartment
is more susceptible to stress response and more prone to malignant
transformation, with the two processes likely interconnected with each other.
Whether these aberrations are only linked to the hematopoietic compartment or
also extend to the surrounding microenvironment is unresolved so far. In the
present protocol we will study hematopoietic stem and progenitor cells (HSPC)
in conjunction with the surrounding mesenchymal stem cells (MSC) focused on (a)
mechanisms that contribute to the increased vulnerability of HSPC for
chemotherapy and (b) defining molecular markers that contribute to the
increased incidence of malignant transformation.
Study objective
The present study will be focused on defining the mechanisms that contribute to
the increased vulnerability of HSPC for chemotherapy. In particular DNA damage
response, ROS production and protective mechanism against stress response
(NFR2) will be studied at RNA and protein level. In addition, the protective
role of MSCs will be analyzed in these processes. To define molecular defects
that contribute to these interactions, DNA will be collected from myeloid and T
cells. The DNA will be studied by targeting sequencing for the most prevalent
mutations that have been demonstrated in AML/MDS.
Study design
Bone marrow cells (20 ml) will be collected from patients at least 1 year
following an ASCT and will be analyzed for a number of in vitro parameters.
Study burden and risks
The bone marrow aspiration is according to standard procedure. It causes a
short pain when the local anasthetic is administered and short pain when the
bone marrow sample is collected.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
-Patients diagnosed with lymphoma or myeloma that have been treated with ASCT.
-At least 1 year following ASCT
-Age >18 years
Exclusion criteria
-Age <18 years
-Signs of active disease related to lymphoma or myeloma
-Pregnancy
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL53260.042.15 |