Real world data on histological transformation in patients with follicular lymphoma: incidence, clinico-pathological risk factors and outcome in a nationwide Danish cohort.

We investigated incidence, risk factors and outcome for follicular lymphoma (FL) patients with histologic transformation (HT) found at primary diagnosis (discordant/composite, dc-tFL) or sequentially (s-tFL). Between 2000 and 2015, 2773 patients were identified. The majority of patients (2252, 81%) did not experience HT (nt-FL), while 224 (8%) had dc-tFL and 297 (11%) s-tFL. The risk of HT was 2.2% per year and 9.6% at 5 years. Age ≥60, a high FLIPI risk score and LDH-elevation were associated with increased risk of HT. Calculated from primary diagnosis and compared with nt-FL, 5-year overall survival (OS) was inferior in both s-tFL and dc-tFL (nt-FL: 82%, s-tFL: 68%, dc-tFL: 68%; p = .001), whereas 5-year progression-free survival (PFS) was worse only in s-tFL (s-tFL: 18%, dc-tFL: 58%, nt-FL: 60%). Calculated from time of HT, s-tFL had inferior outcome compared to dc-tFL for both OS (s-tFL: 47%, dc-tFL: 68%, p = .001) and PFS (s-tFL: 35%, dc-tFL: 58%, p = .001).

Molecular characterization of sorted malignant B cells from patients clinically identified with mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a tumor with a poor prognosis. A few studies have examined the molecular landscape by next-generation sequencing and provided valuable insights into recurrent lesions driving this heterogeneous cancer. However, none has attempted to cross-link the individual genomic and transcriptomic profiles in sorted MCL cells to perform individual molecular characterizations of the lymphomas. Such approaches are relevant as MCL is heterogenous by nature, and thorough molecular diagnostics may potentially benefit the patient with more focused treatment options. In the work described here, we used sorted lymphoma cells from four patients at diagnosis and relapse by intersecting the coding DNA and mRNA. Even though only a few patients were included, this method enabled us to pinpoint a specific set of expressed somatic mutations, to present an overall expression profile different from the normal B cell counterparts, and to track molecular aberrations from diagnosis to relapse. Changes in single-nucleotide coding variants, subtle clonal changes in large-copy-number alterations, subclonal involvement, and changes in expression levels in the clinical course provided detailed information on each of the individual malignancies. In addition to mutations in known genes (e.g., TP53, CCND1, NOTCH1, ATM), we identified others, not linked to MCL, such as a nonsense mutation in SPEN and an MYD88 missense mutation in one patient, which along with copy number alterations exhibited a molecular resemblance to splenic marginal zone lymphoma. The detailed exonic and transcriptomic portraits of the individual MCL patients obtained by the methodology presented here could help in diagnostics, surveillance, and potentially more precise usage of therapeutic drugs by efficient screening of biomarkers.

SOX11 as a minimal residual disease marker for Mantle cell lymphoma.

Recent studies have identified SOX11 as a novel diagnostic marker for mantle cell lymphoma (MCL). We quantified SOX11 by a truly mRNA specific qPCR assay in longitudinal peripheral blood samples from 20 patients and evidenced a close relationship of SOX11 expression and clinical status of the patients. In eight patient courses we validated the expression of SOX11 using t(11;14) and demonstrated positive correlation of SOX11 and t(11;14) levels. To the best of our knowledge this is the first report stating that quantification of SOX11 can be used as an minimal residual disease marker equal to the key translocation t(11;14) in MCL.

A highly sensitive and specific qPCR assay for quantification of the biomarker SOX11 in mantle cell lymphoma.

OBJECTIVES: Mantle cell lymphoma (MCL) is one of the most heterogeneous lymphoid neoplasms with a variable course of disease. Although t(11;14)(q13;q32) is the hallmark of MCL resulting in cyclin D1 (CCND1) overexpression in 90% of patients, this is difficult to validate by immunohistochemistry. We hypothesised that SOX11 could be a robust molecular biomarker for MCL. METHODS: We have developed very sensitive and specific RT-qPCR assay employing a poly-A specific RT primer to circumvent contamination from gDNA caused by the intron-less nature of SOX11. RESULTS: We found a significant difference between the expression levels of SOX11 in patients with MCL at diagnosis (n = 21) and in healthy donors (n = 18) (blood: P < 0.0001; marrow: P = 0.0001). SOX11 expression of very low levels close to the assay sensitivity was detected in only 2 of 18 healthy donors, while low levels of CCND1 expression was observed in all blood and 12 of 13 marrow samples within the defined detection limit of Cq = 40. In spiking experiments of the GRANTA-519 MCL cell line into mononuclear cells from normal donor, the sensitivity of the SOX11 assay was found to be 2 × 10(-4) , while the sensitivity of the CCND1 assay was estimated to 2 × 10(-3) because of the normal background expression. In longitudinal sampling from patients with MCL the minimal residual disease (MRD) values based on the SOX11 expression mirrored the clinical disease development. CONCLUSION: This SOX11 RT-qPCR assay could be a useful tool for MRD monitoring in patients with MCL.