Dataset Information

Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis.

ABSTRACT: We evaluated the prognostic impact of clonal circulating plasma cells (cPCs) detected by six-color multi-parametric flow cytometry (MFC) in light chain (AL) amyloidosis at diagnosis. Of the 154 patients who underwent MFC, cPCs were detected in 42% (n = 65) patients. Median number of cPCs was 81 per 150,000 events (range: 6-17,844). High bone marrow plasma cell percentage was an independent predictor of presence of cPCs. Presence of cPCs at diagnosis was associated with inferior overall survival (OS) (90 vs. 98 months, p = 0.003) and inferior progression free survival (PFS) (31 vs. 52 months, p = 0.02). Estimated 1, 2 and 5 year OS in the two groups was: 74, 64 and 57 and 89, 87, and 80%, respectively. Estimated PFS at 1, 2, and 5 years was: 69, 56, and 23% and 80, 74, and 37%, respectively. Furthermore, the presence of cPCs at diagnosis was an independent adverse predictor of OS in multivariable analysis. Achieving a very-good partial response, or better, was able to overcome the adverse impact of cPCs at diagnosis. Patients with cPCs at diagnosis may warrant closer monitoring post-treatment, especially if they do not achieve a deep hematologic response.

SUBMITTER: Sidana S

PROVIDER: S-EPMC5992020 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis.

Sidana Surbhi S Tandon Nidhi N Dispenzieri Angela A Gertz Morie A MA Dingli David D Jevremovic Dragan D Morice William G WG Kapoor Prashant P Kourelis Taxiarchis V TV Lacy Martha Q MQ Hayman Suzanne R SR Buadi Francis K FK Leung Nelson N Go Ronald S RS Lin Yi Y Russell Stephen J SJ Lust John A JA Zeldenrust Steven R SR Warsame Rahma R Hwa Yi L YL Hobbs Miriam M Fonder Amie A Kyle Robert A RA Rajkumar S Vincent SV Kumar Shaji K SK Gonsalves Wilson I WI

Leukemia 20180221 6

We evaluated the prognostic impact of clonal circulating plasma cells (cPCs) detected by six-color multi-parametric flow cytometry (MFC) in light chain (AL) amyloidosis at diagnosis. Of the 154 patients who underwent MFC, cPCs were detected in 42% (n = 65) patients. Median number of cPCs was 81 per 150,000 events (range: 6-17,844). High bone marrow plasma cell percentage was an independent predictor of presence of cPCs. Presence of cPCs at diagnosis was associated with inferior overall survival ...[more]

PMID: 29483709

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Project description:Immunoglobulin light-chain amyloidosis (AL) is a rare clonal plasma cell (PC) disorder that remains largely incurable. AL and multiple myeloma (MM) share the same cellular origin, but while knowledge about MM PC biology has improved significantly, the same does not apply for AL. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 22 newly-diagnosed AL patients. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and MGUS or MM patients. However, in contrast to MM, highly-purified FACSs-sorted clonal PCs in AL (n=9/22) show virtually normal transcriptomes with only 68 deregulated genes as compared to normal PCs, including a few tumor suppressor (CDH1, RCAN) and pro-apoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11/22) were genomically unstable with a median of 9 copy-number-abnormities (CNAs) per case; many of which similar to those found in MM. Whole-exome sequencing (WES) was performed in three AL patients and revealed a median of 10 non-recurrent mutations per case. Altogether, we showed that although clonal PCs in AL display phenotypic and CNA profiles similar to MM, their transcriptome is remarkably similar to that of normal PCs. First-ever WES revealed the lack of a unifying mutation in AL A total of 22 patients with confirmed diagnosis of AL based on the presence of amyloid-related systemic syndrome, positive amyloid tissue staining with Congo red, and evidence of PC clonality were studied. Samples were collected after informed consent was given, in accordance with local ethical committee guidelines and the Helsinki Declaration. GEP was performed in 9/22 AL cases with adequate RNA extracted from FACS-purified clonal PCs according to patient-specific aberrant phenotypes, and compared to that of normal PCs from 5 healthy individuals (FACSAriaIIb, BDB; â¥95% purity). RNA was hybridized to the Human Gene 1.0 ST Array (Affymetrix, Santa Clara, CA, USA) and normalization was carried using the expression console (Affymetrix) with the RMA algorithm which includes background correction, normalization and calculation of expression values (log2). Differentially expressed genes between classes were identified using the Significant Analysis of Microarrays (SAM) algorithm (http://www-stat.standford.edu/-tibs/SAM), and significant genes were selected based on the lowest q-value (<10-5).

Project description:Immunoglobulin light-chain amyloidosis (AL) is a rare clonal plasma cell (PC) disorder that remains largely incurable. AL and multiple myeloma (MM) share the same cellular origin, but while knowledge about MM PC biology has improved significantly, the same does not apply for AL. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 22 newly-diagnosed AL patients. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and MGUS or MM patients. However, in contrast to MM, highly-purified FACSs-sorted clonal PCs in AL (n=9/22) show virtually normal transcriptomes with only 68 deregulated genes as compared to normal PCs, including a few tumor suppressor (CDH1, RCAN) and pro-apoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11/22) were genomically unstable with a median of 9 copy-number-abnormities (CNAs) per case; many of which similar to those found in MM. Whole-exome sequencing (WES) was performed in three AL patients and revealed a median of 10 non-recurrent mutations per case. Altogether, we showed that although clonal PCs in AL display phenotypic and CNA profiles similar to MM, their transcriptome is remarkably similar to that of normal PCs. First-ever WES revealed the lack of a unifying mutation in AL A total of 22 patients with confirmed diagnosis of AL based on the presence of amyloid-related systemic syndrome, positive amyloid tissue staining with Congo red, and evidence of PC clonality were studied. Samples were collected after informed consent was given, in accordance with local ethical committee guidelines and the Helsinki Declaration. Genome-wide detection of CNAs and copy-number neutral loss-of-heterozygosity (LOH) were investigated using the Cytoscan 750K platform (Affymetrix) in 11/22 cases with adequate DNA extracted from FACS-sorted clonal PCs and paired T-lymphocytes. The AGCC and ChAS software programs (Affymetrix) were used for data analysis as described elsewhere. CNAs were reported when the three following criteria were met: â¥25 consecutive imbalanced markers per segment; â¥100Kb minimum genomic size and; <50% overlap with paired control DNA and/or genomic variants of Toronto DB (DGV). Only CNN-LOH larger that 5Mb, with â¥25 consecutive imbalanced markers per segment, and <50% overlap with patient-paired CNAs were considered.

Dataset Information

Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis.

Publications

Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis.

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