| 1. |
- Agathangelidis, Andreas, et al.
(author)
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Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia : a molecular classification with implications for targeted therapies
- 2012
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:19, s. 4467-4475
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Journal article (peer-reviewed)abstract
- Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1: 2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.
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| 2. |
- Gunnarsson, Rebeqa, et al.
(author)
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Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia
- 2011
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In: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 96:8, s. 1161-1169
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Journal article (peer-reviewed)abstract
- Background High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution. Design and Methods We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years. Results At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV. Conclusions Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
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| 3. |
- Kimby, Eva, et al.
(author)
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Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a : a randomized phase II study from the Nordic Lymphoma Group
- 2008
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In: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 49:1, s. 102-112
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Journal article (peer-reviewed)abstract
- The purpose of this phase II randomized trial was to evaluate the effect and safety of interferon-alpha2a (IFN) in combination with extended dosing rituximab in patients with symptomatic, advanced indolent lymphoma responding to a standard single course of rituximab. Totally 123 patients were treated with rituximab 375 mg/m2 once weekly for 4 weeks leading to 14 complete response (CR; 11%), 56 partial response (PR; 46%), and 13 minor responses (MR; 11%). Patients achieving either PR or MR were randomized to four more infusions of rituximab alone (n = 36) or in combination with five weeks of IFN (n = 33), with an overall response rate (CR + PR) of 78% and 94%, respectively. Significantly more patients in the combination arm improved their response from PR/MR to CR (P < 0.05) and more maintained their responses for > or = 24 months (72% versus 50%), respectively. Overall, 26 out of the 52 patients who achieved CR underwent minimal residual disease (MRD) evaluation. Totally 17 of these (65%) achieved MRD negativity, 14 of whom remain in CR after 4.8 years' follow-up. The addition of IFN to rituximab was generally safe, but reversible thrombocytopenia and neutropenia were noted in one and six patients, respectively, requiring a reduction in the IFN dose. Extended rituximab is effective and well tolerated and combination with IFN seems to improve both the quality and duration of the responses, providing the opportunity to achieve long-term molecular CRs and prolonged failure-free survival without chemotherapy.
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| 4. |
- Sevov, Marie, et al.
(author)
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Longitudinal study of RNA-based prognostic markers in chronic lymphocytic leukemia reveals LPL as the most stable
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Other publication (other academic/artistic)abstract
- Several genes display differential expression in prognostic subsets in chronic lymphocytic leukemia (CLL), including LPL, TCL1, ZAP70 and MCL1. CLL patients commonly have an indolent course with low stage disease and long survival, and in this study we aimed to investigate the stability of RNA-based prognostic markers in such an indolent cohort over time. mRNA expression of LPL, TCL1, ZAP70 and MCL1 was measured in sequential unsorted samples obtained from 96 CLL patients at both diagnosis and a median follow-up of seven years. LPL was the only RNA-based marker that did not demonstrate any significant changes in expression in diagnostic vs. follow-up samples. Furthermore, an 82% concordance between both time-points was observed when grouping cases based on high or low expression. LPL expression was not affected by treatment and in addition, LPL expression in follow-up samples could predict overall survival. In contrast, TCL1 expression was found to increase at follow-up, especially in cases displaying low expression at diagnosis. As TCL1 promotes cell survival this increase could possibly be of importance for progression of the disease. Both ZAP70 and MCL1 mRNA expression were found to vary significantly during the disease course. In summary, using unsorted CLL samples, we have demonstrated that LPL is superior to other RNA-based markers based on stability over time. These findings fully endorse the use of LPL analysis at any time point of the disease.
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