To test the hypothesis that CLL depend on their cognate BCR ligands for growth and/or survival and that lowering specific antigenic pressure decreases the activation status of the leukemia clone resulting in a decrease in tumor burden.
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Decrease in clone size
* Decrease in activation status of CLL cells
Secondary outcome
not applicable
Background summary
B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in western
adults1, is an incurable clonal expansion of CD5+CD19+ B lymphocytes. The
B-cell receptor (BCR) has a prominent role in the pathogenesis of this disease,
indicated by the prognostic value of the somatic hypermutation (SHM) status of
the immunoglobulin (Ig) heavy chain variable gene (IGHV)2,3. Over 30% of CLL
cases can be grouped in subsets based on the stereotypic complementary
determining region 3 (CDR3) amino acid sequences of the expressed IGHV1, 4-9,
strongly suggesting that BCR recognition of particular antigens is instrumental
for oncogenic transformation. In a recent study, it was reported that CLL have
ongoing BCR-signaling within proliferation centers10, suggesting that
recognition of particular antigens may drive tumor expansion.
We recently discovered a new CLL homology subset expressing mutated IGHV3-7
rearrangements paired to IGKV2-24 encoded light chains. We show that these
stereotypic BCRs are highly specific for a carbohydrate structure, abundantly
present in the cell wall of commensal yeasts and molds. Moreover, CLL cells
expressing these stereotypic receptors are induced to proliferate in the
presence of this natural ligand. To our knowledge, this study is the first to
establish a group of common pathogens as functional ligands for BCRs of B-cell
lymphomas and provides a rationale for antigen-targeted therapies.
Study objective
To test the hypothesis that CLL depend on their cognate BCR ligands for growth
and/or survival and that lowering specific antigenic pressure decreases the
activation status of the leukemia clone resulting in a decrease in tumor
burden.
Study design
Three patients, harboring a CLL with mutated IGHV3-7 rearrangements paired to
IGKV2-24 encoded light chains with proven reactivity to yeast and moulds, will
be treated for six weeks with posaconazole. Posaconazole levels will be
measured every two weeks (2 time points). Before treatment, immediately after
treatment and 30 days after treatment blood will be drawn for laboratory
analysis.
Intervention
Patients have to take 3 times daily one tablet of posaconazole for a period of
six weeks
Study burden and risks
Patients have to take 3 times daily one tablet of posaconazole for a period of
six weeks. Blood needs to be drawn at 5 time points.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
* Diagnosis of CLL / MBL with mutated IGHV3-7 rearrangements paired to IGKV2-24 encoded light chains;
* Age 18-80 years
* No CLL related treatment during the last 3 months;
* Able to adhere to the study visit schedule and other protocol requirements;
* WHO performance status of * 2;
* Laboratory test results within these ranges: absolute neutrophil count * 1.0 x 109/l, platelet count * 30 x 109/l, creatinine clearance * 60 ml/min, total bilirubin * 25 µmol/L, AST & ALT * 2 x ULN;
* Written informed consent.
Exclusion criteria
* Known hypersensitivity and/or serious adverse reactions to posaconazole or similar drugs
* Concomitant anti-yeast/mould medication;
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR2012-002041-38-NL |
| CCMO | NL40610.018.12 |