109 research outputs found
Presence of autoimmune disease affects not only risk but also survival in patients with Bâcell nonâHodgkin lymphoma
Although autoimmune diseases (AIDs) are known to predispose to nonâHodgkin lymphoma
(NHL), their association with NHL prognosis has rarely been investigated. We examined
associations between autoimmunity and Bâcell NHL onset by comparing AID history
(determined by selfâreport and medication review and supplemented by chart review where
possible) among 435 adult BâNHL patients in HadassahâHebrew University Medical Center,
diagnosed 2009â2014, and 414 ageâandâsex frequencyâmatched controls. We examined AIDs
as a whole, Bâ and Tâcellâmediated AIDs, and autoimmune thyroid diseases. Among cases,
we used KaplanâMeier and Cox regression models to assess the association of AID with overall
survival and relapseâfree survival, adjusting for prognostically important patient and disease
characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and
histological subgroup.
Autoimmune diseases were associated with BâNHL (odds ratio [OR] = 1.95; 95% confidence
interval (CI), 1.31â2.92), especially AIDs mediated by Bâcell activation (OR = 5.20; CI, 1.90â14.3),
which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59â80.9). We
found that time to relapse for all BâNHL patients with AIDs was significantly shorter (mean
of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted
hazard ratio [HRadj] = 1.69 (CI, 1.03â2.79). Specifically, in patients with diffuse large Bâcell
lymphoma, of whom 91.8% had received rituximab, a history of Bâcellâmediated AIDs was
associated with shorter relapseâfree survival and overall survival, HRadj = 8.34 (CI, 3.01â
23.1) and HRadj = 3.83 (CI, 1.20â12.3), respectively.
Beyond confirming the wellâknown association between AIDs and BâNHL, we found that AID is
an adverse prognostic factor in Bâcell lymphoma, associated with a shortened time to relapse,
suggesting that there are specific therapeutic challenges in the subgroup of patients suffering
from both these diseases. Further work is required to address mechanisms of resistance to
standard treatment in the setting of AIDâassociated BâNHL. In the era of immunotherapy, these
findings have particular relevance.This study was made possible by the generous support of the American
people through the United States Agency for International Development
(USAID)/MERC grant no. TAâMOUâ11âM31â025. The contents
are the responsibility of the authors and do not necessarily reflect
the views of USAID or the United States Government; Israel Science
Foundation (ISF) grant no. 877/10; and the Hadassah University
Hospital Compensatory Fund. We thank Noemie Cohen for data entry
Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation
Biomarcadors; Ibrutinib; Limfoma no hodgkinBiomarkers; Ibrutinib; Non-hodgkin's lymphomaBiomarcadores; Ibrutinib; Linfoma no hodgkinWe analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p =âŻ0.065; complete response 37.5% vs. 0%; p =âŻ0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p =âŻ0.055), KLHL14 (30.0% vs. 0%; p =âŻ0.046), and LRP1B (30.0% vs. 6.2%; p =âŻ0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88 , or TNFRSF14 , while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p =âŻ0.047) and ROS1 (0% vs. 50.0%; p =âŻ0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cellâlike DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.Sponsored by Janssen Research & Development, LLC
Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation
We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell-like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivoluma
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Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma
Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13â1.43, p = 6.77Ă10â5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34â0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL
Health-related quality-of-life results from the phase 3 OPTIMISMM study: pomalidomide, bortezomib, and low-dose dexamethasone versus bortezomib and low-dose dexamethasone in relapsed or refractory multiple myeloma
This is an accepted manuscript of an article published by Taylor & Francis in Leukemia & Lymphoma on 09/04/2020, available online: https://www.tandfonline.com/doi/full/10.1080/10428194.2020.1747066
The accepted version of the publication may differ from the final published version.In the randomized phase-3 OPTIMISMM study, the addition of pomalidomide to bortezomib and low-dose dexamethasone (PVd) resulted in significant improvement in progression-free survival (PFS) in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM), including lenalidomide refractory patients. Here, we report health-related quality of life (HRQoL) results from this trial. Patients received PVd or Vd in 21-day cycles until disease progression or discontinuation. HRQoL was assessed using the EORTC QLQ-C30, QLQ-MY20, and EQ-5D-3L instruments on day 1 of each treatment cycle. Mean score changes for global QoL, physical functioning, fatigue, side effects of treatment domains, and EQ-5D-3L index were generally stable over time across treatment arms. The proportion of patients who experienced clinically meaningful worsening in global QoL and other domains of interest was similar. These HRQoL results with PVd along with previously demonstrated improvement in PFS vs Vd continue to support its use in patients with RRMM.This work was supported by Celgene Corporation.Published versio
Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma
Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients
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Cutaneous and Subcutaneous Necrosis following DexrazoxaneâCHOP Therapy
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