DIAGNOSTICS AND PROGNOSTIC STRATIFICATION OF PATIENTS WITH WALDENSTRÖM’S MACROGLOBULINEMIA – SINGLE CENTRE EXPERIENCE
(Abstract release date: 05/19/16)
EHA Library. Krupkova L. 06/09/16; 132875; E1326
Mrs. Lenka Krupkova
Contributions
Contributions
Abstract
Abstract: E1326
Type: Eposter Presentation
Background
Waldenström’s macroglobulinemia (WM) is a rare B-cell neoplasm defined as lymphoplasmacytic lymphoma with bone marrow infiltration and monoclonal IgM in the serum. More than 90% of WM patients carry a point mutation L265P in the MYD88 gene and concurrently, almost one third of MYD88L265P-positive patients harbor frameshift (WHIM-FS) or non-sense (WHIM-NS) mutation in gene CXCR4. The mutations in CXCR4 result in premature stop codons and in shortening of CXCR4 protein product. Incomplete C-terminal domain of CXCR4 chemokine receptor is known to hyperactivate CXCR4-mediated signalization. The presence and type of mutation in genes MYD88 and CXCR4 appears to be significant in diagnostics and prognostic stratification of WM patients and it also influences the clinical manifestation of the disease.
Aims
To analyze mutational status of MYD88 and CXCR4 genes in patients with WM, to compare our results with laboratory parameters and to evaluate the prognostic stratification of the patients according to MYD88 and CXCR4 mutational status.
Methods
Analyzed DNA was isolated from mononuclear fraction of bone marrow cells at the time of diagnosis. Mutational status of analyzed genes was determined using allele-specific PCR (in the case of MYD88) and using direct Sanger sequencing (in the case of CXCR4). All found mutations were confirmed by specific cleavage with restriction endonucleases at defined conditions.
Results
We analyzed a group of patients with WM (n=16). We identified 15 MYD88L265P-positive patients (93.8%), and 4 of them (25%) were also CXCR4 mutants (1 patient harbored WHIM-FS mutation and 3 harbored WHIM-NS mutation). CXCR4 mutations were associated with more aggressive disease (higher IPSS score, pancytopenia, higher levels of paraprotein and free light chains in serum, higher bone marrow infiltration; Table 1), and CXCR4WHIM-WT patients were often asymptomatic. CXCR4 mutations were also associated with worse treatment response (2 CXCR4WHIM-MUT patients were resistant and 2 patients had a partial response to first-line therapy).Table 1: The medians of laboratory parameters of the WM patients with and without CXCR4 mutation.
Conclusion
The mutational analysis of MYD88 and CXCR4 genes is essential for the diagnostics and prognostic stratification of patients with WM and it allows a deeper understanding of the molecular pathogenesis of the disease. In accordance with published data, we confirmed that CXCR4 mutations are associated with more aggressive disease presentation and thus affect treatment outcome. This work was supported by grant IGA-LF-2016-001.
Session topic: E-poster
Keyword(s): CXCR4, Mutation analysis, Waldenstrom's macroglobulinemia
Type: Eposter Presentation
Background
Waldenström’s macroglobulinemia (WM) is a rare B-cell neoplasm defined as lymphoplasmacytic lymphoma with bone marrow infiltration and monoclonal IgM in the serum. More than 90% of WM patients carry a point mutation L265P in the MYD88 gene and concurrently, almost one third of MYD88L265P-positive patients harbor frameshift (WHIM-FS) or non-sense (WHIM-NS) mutation in gene CXCR4. The mutations in CXCR4 result in premature stop codons and in shortening of CXCR4 protein product. Incomplete C-terminal domain of CXCR4 chemokine receptor is known to hyperactivate CXCR4-mediated signalization. The presence and type of mutation in genes MYD88 and CXCR4 appears to be significant in diagnostics and prognostic stratification of WM patients and it also influences the clinical manifestation of the disease.
Aims
To analyze mutational status of MYD88 and CXCR4 genes in patients with WM, to compare our results with laboratory parameters and to evaluate the prognostic stratification of the patients according to MYD88 and CXCR4 mutational status.
Methods
Analyzed DNA was isolated from mononuclear fraction of bone marrow cells at the time of diagnosis. Mutational status of analyzed genes was determined using allele-specific PCR (in the case of MYD88) and using direct Sanger sequencing (in the case of CXCR4). All found mutations were confirmed by specific cleavage with restriction endonucleases at defined conditions.
Results
We analyzed a group of patients with WM (n=16). We identified 15 MYD88L265P-positive patients (93.8%), and 4 of them (25%) were also CXCR4 mutants (1 patient harbored WHIM-FS mutation and 3 harbored WHIM-NS mutation). CXCR4 mutations were associated with more aggressive disease (higher IPSS score, pancytopenia, higher levels of paraprotein and free light chains in serum, higher bone marrow infiltration; Table 1), and CXCR4WHIM-WT patients were often asymptomatic. CXCR4 mutations were also associated with worse treatment response (2 CXCR4WHIM-MUT patients were resistant and 2 patients had a partial response to first-line therapy).Table 1: The medians of laboratory parameters of the WM patients with and without CXCR4 mutation.
| MYD88MUT CXCR4WHIM-WT | MYD88MUT CXCR4WHIM-MUT | |
| Paraprotein level [g/l] | 14.3 (3.7-32.2) | 25.4 (10.6-30.9) |
| Bone marrow infiltration [%] | 25 (10-72.4) | 64 (10-96) |
| Involved free light chain level [mg/l] | 103.5 (26-633) | 341 (317-507) |
| IPSS | 1 (n=6); 2 (n=5);3 (n=1) | 2 (n=1); 3 (n=3) |
| Hemoglobin [g/l] | 112.5 (89-149) | 111.0 (90-117) |
| Thrombocytes [x109/l] | 258 (37-585) | 189 (15-281) |
Conclusion
The mutational analysis of MYD88 and CXCR4 genes is essential for the diagnostics and prognostic stratification of patients with WM and it allows a deeper understanding of the molecular pathogenesis of the disease. In accordance with published data, we confirmed that CXCR4 mutations are associated with more aggressive disease presentation and thus affect treatment outcome. This work was supported by grant IGA-LF-2016-001.
Session topic: E-poster
Keyword(s): CXCR4, Mutation analysis, Waldenstrom's macroglobulinemia
Abstract: E1326
Type: Eposter Presentation
Background
Waldenström’s macroglobulinemia (WM) is a rare B-cell neoplasm defined as lymphoplasmacytic lymphoma with bone marrow infiltration and monoclonal IgM in the serum. More than 90% of WM patients carry a point mutation L265P in the MYD88 gene and concurrently, almost one third of MYD88L265P-positive patients harbor frameshift (WHIM-FS) or non-sense (WHIM-NS) mutation in gene CXCR4. The mutations in CXCR4 result in premature stop codons and in shortening of CXCR4 protein product. Incomplete C-terminal domain of CXCR4 chemokine receptor is known to hyperactivate CXCR4-mediated signalization. The presence and type of mutation in genes MYD88 and CXCR4 appears to be significant in diagnostics and prognostic stratification of WM patients and it also influences the clinical manifestation of the disease.
Aims
To analyze mutational status of MYD88 and CXCR4 genes in patients with WM, to compare our results with laboratory parameters and to evaluate the prognostic stratification of the patients according to MYD88 and CXCR4 mutational status.
Methods
Analyzed DNA was isolated from mononuclear fraction of bone marrow cells at the time of diagnosis. Mutational status of analyzed genes was determined using allele-specific PCR (in the case of MYD88) and using direct Sanger sequencing (in the case of CXCR4). All found mutations were confirmed by specific cleavage with restriction endonucleases at defined conditions.
Results
We analyzed a group of patients with WM (n=16). We identified 15 MYD88L265P-positive patients (93.8%), and 4 of them (25%) were also CXCR4 mutants (1 patient harbored WHIM-FS mutation and 3 harbored WHIM-NS mutation). CXCR4 mutations were associated with more aggressive disease (higher IPSS score, pancytopenia, higher levels of paraprotein and free light chains in serum, higher bone marrow infiltration; Table 1), and CXCR4WHIM-WT patients were often asymptomatic. CXCR4 mutations were also associated with worse treatment response (2 CXCR4WHIM-MUT patients were resistant and 2 patients had a partial response to first-line therapy).Table 1: The medians of laboratory parameters of the WM patients with and without CXCR4 mutation.
Conclusion
The mutational analysis of MYD88 and CXCR4 genes is essential for the diagnostics and prognostic stratification of patients with WM and it allows a deeper understanding of the molecular pathogenesis of the disease. In accordance with published data, we confirmed that CXCR4 mutations are associated with more aggressive disease presentation and thus affect treatment outcome. This work was supported by grant IGA-LF-2016-001.
Session topic: E-poster
Keyword(s): CXCR4, Mutation analysis, Waldenstrom's macroglobulinemia
Type: Eposter Presentation
Background
Waldenström’s macroglobulinemia (WM) is a rare B-cell neoplasm defined as lymphoplasmacytic lymphoma with bone marrow infiltration and monoclonal IgM in the serum. More than 90% of WM patients carry a point mutation L265P in the MYD88 gene and concurrently, almost one third of MYD88L265P-positive patients harbor frameshift (WHIM-FS) or non-sense (WHIM-NS) mutation in gene CXCR4. The mutations in CXCR4 result in premature stop codons and in shortening of CXCR4 protein product. Incomplete C-terminal domain of CXCR4 chemokine receptor is known to hyperactivate CXCR4-mediated signalization. The presence and type of mutation in genes MYD88 and CXCR4 appears to be significant in diagnostics and prognostic stratification of WM patients and it also influences the clinical manifestation of the disease.
Aims
To analyze mutational status of MYD88 and CXCR4 genes in patients with WM, to compare our results with laboratory parameters and to evaluate the prognostic stratification of the patients according to MYD88 and CXCR4 mutational status.
Methods
Analyzed DNA was isolated from mononuclear fraction of bone marrow cells at the time of diagnosis. Mutational status of analyzed genes was determined using allele-specific PCR (in the case of MYD88) and using direct Sanger sequencing (in the case of CXCR4). All found mutations were confirmed by specific cleavage with restriction endonucleases at defined conditions.
Results
We analyzed a group of patients with WM (n=16). We identified 15 MYD88L265P-positive patients (93.8%), and 4 of them (25%) were also CXCR4 mutants (1 patient harbored WHIM-FS mutation and 3 harbored WHIM-NS mutation). CXCR4 mutations were associated with more aggressive disease (higher IPSS score, pancytopenia, higher levels of paraprotein and free light chains in serum, higher bone marrow infiltration; Table 1), and CXCR4WHIM-WT patients were often asymptomatic. CXCR4 mutations were also associated with worse treatment response (2 CXCR4WHIM-MUT patients were resistant and 2 patients had a partial response to first-line therapy).Table 1: The medians of laboratory parameters of the WM patients with and without CXCR4 mutation.
| MYD88MUT CXCR4WHIM-WT | MYD88MUT CXCR4WHIM-MUT | |
| Paraprotein level [g/l] | 14.3 (3.7-32.2) | 25.4 (10.6-30.9) |
| Bone marrow infiltration [%] | 25 (10-72.4) | 64 (10-96) |
| Involved free light chain level [mg/l] | 103.5 (26-633) | 341 (317-507) |
| IPSS | 1 (n=6); 2 (n=5);3 (n=1) | 2 (n=1); 3 (n=3) |
| Hemoglobin [g/l] | 112.5 (89-149) | 111.0 (90-117) |
| Thrombocytes [x109/l] | 258 (37-585) | 189 (15-281) |
Conclusion
The mutational analysis of MYD88 and CXCR4 genes is essential for the diagnostics and prognostic stratification of patients with WM and it allows a deeper understanding of the molecular pathogenesis of the disease. In accordance with published data, we confirmed that CXCR4 mutations are associated with more aggressive disease presentation and thus affect treatment outcome. This work was supported by grant IGA-LF-2016-001.
Session topic: E-poster
Keyword(s): CXCR4, Mutation analysis, Waldenstrom's macroglobulinemia
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