| 11. |
- Husby, Simon, et al.
(författare)
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miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 125:17, s. 2669-2677
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2trial (screening cohort). Prognosticmi RNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.
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| 12. |
- Kofoed Damm, Jesper, et al.
(författare)
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Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo.
- 2015
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Ingår i: Experimental hematology & oncology. - : Springer Science and Business Media LLC. - 2162-3619. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma.
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| 13. |
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| 14. |
- Kolstad, Arne, et al.
(författare)
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Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years
- 2017
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Ingår i: Biology of blood and marrow transplantation. - : ELSEVIER SCIENCE INC. - 1083-8791 .- 1523-6536. ; 23:3, s. 428-435
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Tidskriftsartikel (refereegranskat)abstract
- The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rear-rangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P <.0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P <.0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.
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| 15. |
- Kolstad, Arne, et al.
(författare)
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Nordic MCL-3 study : 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 123:19, s. 2953-2959
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Tidskriftsartikel (refereegranskat)abstract
- The main objective of the MCL3 study was to improve outcome for patients not in CR before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. 160 consecutive, untreated stage II-IV MCL patients < 66 years received rituximab (R)- maxi-CHOP alternating with R-high-dose Ara-C (6 cycles total), followed by high-dose BEAM or BEAC and autologous stem cell transplantation 2005-2009. Zevalin (0.4 mCi/kg) was given to responders in only CRu/PR prior to high-dose therapy. The overall response rate (ORR) pre-transplant was 97%. After a median follow-up of 4.4 years the outcome did not differ from that of the historic control, the MCL2 trial with the same treatment except for Zevalin. Overall (OS), event free (EFS), and progression-free survival (PFS) at 4 years were 78, 62 and 71%, respectively. For patients in CRu/PR before transplant who received Zevalin duration of response was shorter than in the CR group. Inferior PFS, EFS- and OS were predicted by PET-positivity pre-transplant and detectable minimal residual disease (MRD) before and after transplant. In conclusion, a positive PET prior to transplant and MRD are strong predictors of outcome. Late intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant.
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| 16. |
- Linderoth, Johan, et al.
(författare)
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CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma
- 2007
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 48:9, s. 1774-1779
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Tidskriftsartikel (refereegranskat)abstract
- In order to confirm our earlier findings of the prognostic effects of CD23 and CD40 expression in diffuse large B-cell lymphoma (DLBCL), possibly due to association with the germinal center (GC) phenotype and/or an increased autologous tumour response, tumour specimens from 125 patients with de novo DLBCL were investigated for immunohistochemical expression of CD23, CD40, BCL6, CD10, MUM1, CD4 and CD8. CD40 was positive in 64% and was associated with improved overall survival (p = 0.03). A GC phenotype was present in 47%, and was also associated with a better overall survival (p = 0.006) but did not correlate with CD40-expression. There was no correlation between amount of tumour infiltrating T-cells and CD40-positivity. CD23 was positive in 10% and expression did not correlate with prognosis. In conclusion, the prognostic effect of CD40 expression was confirmed, but did not correlate with GC-phenotype or T-cell infiltration.
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| 17. |
- Linderoth, Johan, et al.
(författare)
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Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma
- 2008
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 141:4, s. 423-32
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Tidskriftsartikel (refereegranskat)abstract
- In order to identify genes associated with primary chemotherapy-resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B-cell lymphoma (DLBCL), stage II-IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy-nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM-1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin-3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.
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| 18. |
- Linderoth, Johan, et al.
(författare)
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Tissue microarray is inappropriate for analysis of BCL6 expression in diffuse large B-cell lymphoma
- 2007
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 79:2, s. 146-149
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In this study, our aim was to investigate how different immunohistochemical techniques may influence the result of BCL6 positivity and categorization in germinal center (GC) and non-GC derived diffuse large B-cell lymphoma (DLBCL), as it has been proposed that classification of DLBCL according to cell-of-origin by immunohistochemistry may be performed as a routine procedure in the diagnostic work-up. However, a number of technical issues need to be solved before introducing this as a standard technique. Methods: Tumor specimens from 122 patients with de novo stage II–IV disease, adequately treated with anthracycline-containing chemotherapy regimens were collected. Immunohistochemical expression of BCL6, CD10, and MUM-1/IRF4 was examined using a tissue microarray (TMA) technique. BCL6 and CD10 were also evaluated on whole tissue sections. Results: Due to profound tissue heterogeneity, BCL6 showed a wide range of positivity, with a high number of false negative results by TMA (25% positive), compared to 53% on whole tissue sections (WTS). CD10 was more homogeneously expressed, and TMA results corresponded better to WTS. Consequently, the results from categorization into GC and non-GC DLBCL differed considerably by use of the two methods, and resulted in very different outcome in terms of overall survival. Conclusion: Immunohistochemical GC-status determined on TMA is not reliable enough to be used for individual treatment decisions in DLBCL, mostly due to difficulties in interpreting BCL6 status.
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| 19. |
- Nordström, Lena, et al.
(författare)
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SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma : a Nordic Lymphoma Group study
- 2014
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 166:1, s. 98-108
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment-related morbidity, additional parameters need to be evaluated to enable risk-adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki-67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.
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| 20. |
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