Summary
We explored the relevance of genomic microarrays (GM) in the refinement of prognosis in newly diagnosed low‐risk chronic lymphocytic leukaemia (CLL) patients as defined by isolated del(13q) ...or no lesions by a standard 4 probe fluorescence in situ hybridization (FISH) analysis. Compared to FISH, additional lesions were detected by GM in 27 of the 119 patients (22.7%). The concordance rate between FISH and GM was 87.4%. Discordant results between cytogenetic banding analysis (CBA) and GM were observed in 45/119 cases (37.8%) and were mainly due to the intrinsic characteristics of each technique. The presence of additional lesions by GM was associated with age > 65 years (p = 0.047), advanced Binet stage (p = 0.001), CLL‐IPI score (p < 0.001), a complex karyotype (p = 0.004) and a worse time‐to‐first treatment in multivariate analysis (p = 0.009). Additional lesions by GM were also significantly associated with a worse time‐to‐first treatment in the subset of patients with wild‐type TP53 and mutated IGHV (p = 0.025). In CLL patients with low‐risk features, the presence of additional lesions identified by GM helps to identify a subset of patients with a worse outcome that could be proposed for a risk‐adapted follow‐up and for early treatment including targeted agents within clinical trials.
In newly diagnosed low‐risk CLL patients as defined by a standard 4 probe FISH analysis, additional lesions by GM were detected in 27 out of 119 patients (22.7%). The presence of additional lesions was associated with a shorter TTFT, independently of CLL‐IPI. Additional lesions by GM were also associated with a shorter TTFT in the subset of patients with wild type TP53 and mutated IGHV. In low‐risk CLL, the presence of additional lesions by GM helps to identify a subset of patients with worse outcome that could be proposed for a risk‐adapted follow‐up and early treatments including targeted agents within clinical trials.
Here we evaluated the epigenomic and transcriptomic profile of XPO1 mutant chronic lymphocytic leukaemia (CLL) and their clinical phenotype. By ATAC-seq, chromatin regions that were more accessible ...in XPO1 mutated CLL were enriched of binding sites for transcription factors regulated by pathways emanating from the B-cell receptor (BCR), including NF-κB signalling, p38-JNK and RAS-RAF-MEK-ERK. XPO1 mutant CLL, consistent with the chromatin accessibility changes, were enriched with transcriptomic features associated with BCR and cytokine signalling. By combining epigenomic and transcriptomic data, MIR155HG, the host gene of miR-155, and MYB, the transcription factor that positively regulates MIR155HG, were upregulated by RNA-seq and their promoters were more accessible by ATAC-seq. To evaluate the clinical impact of XPO1 mutations, we investigated a total of 957 early-stage CLL subdivided into 3 independent cohorts (N = 276, N = 286 and N = 395). Next-generation sequencing analysis identified XPO1 mutations as a novel predictor of shorter time to first treatment (TTFT) in all cohorts. Notably, XPO1 mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early-stage prognostic models. These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early-stage CLL.
Among indolent non-Hodgkin lymphomas (iNHLs), the analysis of measurable/minimal residual disease (MRD) has been extensively applied to follicular lymphoma (FL). Treatment combinations have deeply ...changed over the years, as well as the techniques to measure MRD, which is currently evaluated only in the setting of clinical trials. Here, we discuss the evidence on the role of molecular monitoring in the management of FL. Mature data support the quantification of molecular tumor burden at diagnosis as a tool to stratify patients in risk categories and of MRD evaluation at the end of treatment to predict progression-free survival and overall survival. Moreover, MRD deserves further studies as a tool to refine the clinical/metabolic response and to modulate treatment intensity/duration. Patients with a higher relapse probability can be identified, but the relevance of continuous molecular follow-up should be clarified by kinetic models of MRD analysis. Being the BCL2/heavy chain immunoglobulin gene hybrid rearrangement detectable in about 50% to 60% of advanced FL and in 30% of positron emission tomography/computed tomography-staged localized FL, technical advancements such as next-generation sequencing/target locus amplification may allow broadening the FL population carrying a molecular marker. Droplet digital polymerase chain reaction can better quantify MRD at low levels, and novel sources of DNA, such as cell-free DNA, may represent a noninvasive tool to monitor MRD. Finally, MRD in other iNHLs, such as lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and marginal zone lymphoma, is beginning to be explored.
The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients ...receiving R-CHOP, R-FM, or R-CVP.
DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months.
At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden (<1 × 10(-4) copies) showed higher complete remission (CR) rate and longer progression-free survival (PFS; 3-year PFS 80% vs. 59%; P = 0.015). PFS was significantly conditioned by the PCR status at 12 and 24 months, with 3-year PFS of 66% for MRD(-) cases versus 41% for those MRD(+) at 12 months (P = 0.015), and 84% versus 50% at 24 months (P = 0.014). The MRD negativity at 12 and 24 months resulted in an improved PFS both in CR and in partial remission (PR) patients (3-year PFS = 72% for cases CR/PCR(-) vs. 32% for those CR/PCR(+) vs. 62% for those PR/PCR(-) and 25% for patients in PR/PCR(+); P = 0.001). The prognostic value of MRD at 12 and 24 months of follow-up was confirmed also in multivariate analysis.
In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy.
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