scholarly journals Correction of Vitamin D Deficiency in Patients with Aggressive B-Cell Lymphomas during Rituximab-Containing Chemotherapy: Impact on Outcome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3051-3051
Author(s):  
Stefan Hohaus ◽  
Maria Chiara Tisi ◽  
Silvia Bellesi ◽  
Elena Maiolo ◽  
Germana Tartaglia ◽  
...  
Keyword(s):  
Vitamin D ◽  
B Cell ◽  
Vitamin D Deficiency ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Vitamin D Supplementation ◽  
B Cell Lymphomas ◽  
Large B Cell Lymphoma ◽  
Vitamin D Levels ◽  
Large B Cell

Abstract Vitamin D deficiency has been reported to be a risk factor in elderly patients (pts) with diffuse large B cell lymphoma (DLBCL) treated with Rituximab-containing chemotherapy (R-CHOP) (Bittenbring et al, J Clin Oncol 32:3242, 2014). In vitro data suggest that vitamin D supplementation could enhance rituximab-mediated cytotoxicity. In a single-center study, we prospectively measured 25-OH Vitamin D levels at diagnosis in a cohort of 156 pts with aggressive B cell non-Hodgkin lymphoma (DLBCL NOS, 129 pts; primary mediastinal large B cell lymphoma, 9 pts; B cell lymphoma, unclassifiable with intermediate characteristics between DLBCL and Burkitt lymphoma, 8 pts; T-cell/histiocyte-rich large B cell lymphoma, 4 pts; other forms, 6 pts) who were candidates for Rituximab-containing chemotherapy (R-CHOP or equivalent). Pts with deficient/insufficient vitamin D levels were offered supplementation. We used the formula of Singh (JABFM 27:495, 2014) to calculate the need of Vitamin D supplementation. Vitamin D levels were controlled during supplementation. Event Free Survival (EFS) was defined as time from diagnosis to relapse, disease progression or change of therapy for any reason or death. Vitamin D levels were considered deficient (<10 ng/ml) in 52 pts (33%), insufficient (10 to 30 ng/ml) in 86 pts (55%), and normal (>30 to 100 ng/ml) in 18 pts (12%). Looking at pts characteristics, there was no difference in vitamin D levels according to sex (p=0.5), age (p=0.8) or stage (p=0.5), while poor performance status (ECOG > 2) and high LDH levels were significantly associated with lower vitamin D levels (p=0.002 and p=0.0007). We observed a weak, but significant negative correlation between Vitamin D levels and Hb and albumin levels (p=0.003 and p=0.0001, respectively). In addition, there was a significant seasonal variation with lowest vitamin D levels in the second trimester (p=0.001). We implemented an oral substitution regimen with Vitamin D3 (cholecalciferole) to increase vitamin D levels early during treatment. Vitamin D (cholecalciferole 25000 U) was given once a week following a loading phase of daily doses of 25000 U for 1 week in patients with insufficient Vitamin D levels and for 2 weeks with deficient Vitamin D levels. Vitamin D substitution was stopped at end of treatment. This supplementation resulted in substitution of Vitamin D over the treatment period of 4951 U/d in patients with insufficient Vitamin D levels (median of calculated need in 86 pts: 4374 U/d) and of 5612 U/d for patients with deficient Vitamin D levels (median of calculated need 6379 U/d in 52 pts). A total of 116 patients received Vitamin D supplementation. A second determination of Vitamin D levels after a median of 1.7 month in 84 pts showed a significant increase of Vitamin D levels from a median of 17 ng/ml to 33 ng/ml (p=0.001). Supplementation resulted in normalization of Vitamin D levels in 46/84 pts (55%). No episodes of hypervitaminosis or hypercalcemia were observed. We analyzed the prognostic impact of vitamin D levels at diagnosis and after supplementation. Pts with vitamin D levels in the normal range either at diagnosis or due to supplementation (n=61) had a significant better EFS at 18 months when compared to pts with persistently deficient/insufficient vitamin D levels (n=44) (88% versus 77%, p=0.03). Vitamin D levels at diagnosis before supplementation only showed a trend for impact on EFS (p=0.09). We conclude that Vitamin D deficiency is frequent in pts with aggressive B-cell lymphomas also in central Italy. Vitamin D supplementation results in improved vitamin D levels. Our data suggest that outcome in pts with DLBCL treated with rituximab-containing chemotherapy may be improved by vitamin D supplementation. Disclosures No relevant conflicts of interest to declare.

Vitamin D Deficiency Impairs Rituximab-Mediated Cellular Cytotoxicity and Outcome of Patients With Diffuse Large B-Cell Lymphoma Treated With but Not Without Rituximab

2014 ◽  
Vol 32 (29) ◽  
pp. 3242-3248 ◽  
Author(s):  
Jörg Thomas Bittenbring ◽  
Frank Neumann ◽  
Bettina Altmann ◽  
Marina Achenbach ◽  
Jörg Reichrath ◽  
...  
Keyword(s):  
Vitamin D ◽  
Elderly Patients ◽  
B Cell ◽  
Vitamin D Deficiency ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cellular Cytotoxicity ◽  
Large B Cell Lymphoma ◽  
Vitamin D Levels ◽  
Large B Cell

Purpose To investigate the impact and mechanisms of vitamin D deficiency (VDD) on the outcome of elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Three hundred fifty-nine pretreatment 25-hydroxyvitamin D3 (25[OH]D3) serum levels from the RICOVER-60 study (Six Versus Eight Cycles of Biweekly CHOP-14 With or Without Rituximab in Elderly Patients With Aggressive CD20+ B-Cell Lymphomas) and 63 from the RICOVER-noRTh study (an amendment to the RICOVER-60 study in which patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone administered at an interval of 2 weeks plus two cycles of rituximab [R-CHOP-14], but without radiotherapy) were determined by chemoluminescent immunoassay. Rituximab-mediated cellular cytotoxicity (RMCC) was assessed by lactate dehydrogenase release assay of CD20+ Daudi cells. Results RICOVER-60 patients with VDD (≤ 8 ng/mL) and vitamin D levels more than 8 ng/mL treated with rituximab had 3-year event-free survival (EFS) of 59% and 79% and 3-year overall survival (OS) of 70% and 82%, respectively. These differences were significant in a multivariable analysis adjusting for International Prognostic Index risk factors with a hazard ratio (HR) of 2.1 (P = .008) for EFS and 1.9 (P = .040) for OS. EFS was not significantly different in patients with vitamin D levels ≤ 8 or more than 8 ng/mL (HR, 1.2; P = .388) treated without rituximab. This was confirmed in an independent validation set of 63 RICOVER-noRTh patients. RMCC increased significantly (P < .001) in seven of seven individuals with VDD after substitution and normalization of their vitamin D levels. Conclusion VDD is a risk factor for elderly patients with DLBCL treated with R-CHOP. That VDD impairs RMCC and substitution improves RMCC strongly suggests that vitamin D substitution enhances rituximab efficacy, which must be confirmed in appropriately designed prospective trials addressing VDD and substitution not only in DLBCL, but also in malignancies treated with other antibodies, of which the major mechanism of action is antibody-dependent cellular cytotoxicity (eg, trastuzumab in breast cancer and cetuximab in colorectal cancer).

bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related.

1998 ◽  
Vol 16 (6) ◽  
pp. 2080-2085 ◽  
Author(s):  
F A Geelen ◽  
M H Vermeer ◽  
C J Meijer ◽  
S C Van der Putte ◽  
E Kerkhof ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
European Organization ◽  
Clinical Behavior ◽  
Large B Cell Lymphoma ◽  
Cutaneous Lymphomas ◽  
Distinct Disease ◽  
Large B Cell

PURPOSE Primary cutaneous large B-cell lymphoma (PCLBCL) that presents on the leg has recently been recognized as a distinct disease entity. These lymphomas have a reduced disease-free survival and a worse prognosis as compared with the more common, morphologically similar PCLBCL that present on the head or trunk. Studies in noncutaneous diffuse large B-cell lymphomas suggest a relationship between the expression of bcl-2 protein and clinical behavior. In the present study, we investigated whether these two groups of PCLBCL differ in the expression of bcl-2 protein and the presence of t(4;18), known as one of the causes of bcl-2 overexpression. PATIENTS AND METHODS Paraffin sections from pretreatment biopsies of 14 PCLBCLs of the head or trunk and nine PCLBCLs of the legs were investigated for expression of bcl-2 protein using immunohistochemistry, and for the presence of the 14;18 translocation using polymerase chain reaction (PCR) amplification with primers against both the major breakpoint region (mbr) and the minor cluster region (mcr) of bcl-2. For reasons of comparison, nine secondary cutaneous large B-cell lymphomas (SCLBCLs) were also studied. RESULTS Expression of bcl-2 protein was found in all nine PCLBCLs of the leg and in all nine SCLBCLs, but not in any of the 14 PCLBCLs on the head and trunk. The t(14;18) was only detected in two of seven SCLBCLs, but not in the five PCLBCLs of the leg or the eight PCLBCLs on the head or trunk studied. CONCLUSION The striking differences in bcl-2 expression between PCLBCL of the head or trunk and PCLBCL on the leg suggest that bcl-2 expression is site-related and may contribute to the different clinical behavior between these two groups of lymphomas. In addition, they underscore that PCLBCL on the head and trunk and PCLBCL on the leg are distinct disease entities, as recently recognized in the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas.

scholarly journals Grey Zone Lymphomas: Lymphomas with Intermediate Features

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Sylvia Hoeller ◽  
Christiane Copie-Bergman
Keyword(s):  
B Cell ◽  
Who Classification ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
World Health ◽  
Grey Zone ◽  
B Cell Lymphomas ◽  
Large B Cell Lymphoma ◽  
Large B Cell

The current classification of lymphoid neoplasms is based on clinical information, morphology, immunophenotype, and molecular genetic characteristics. Despite technical and scientific progress, some aggressive B-cell lymphomas with features overlapping between two different types of lymphomas remain difficult to classify. The updated 2008 World Health Organization (WHO) classification of Tumours of the Hematopoietic and Lymphoid Tissues has addressed this problem by creation of two new provisional categories of B-cell lymphomas, unclassifiable; one with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma and the second with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. We review here the diagnostic criteria of these two provisional entities and discuss new scientific findings in light of the 2008 WHO classification.

Genomic Rearrangements Involving Programmed Death Ligands Are Recurrent In Primary Mediastinal Large B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 635-635 ◽  
Author(s):  
David D. W. Twa ◽  
Fong Chun Chan ◽  
Susana Ben-Neriah ◽  
Bruce W. Woolcock ◽  
King L. Tan ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Transcript Levels ◽  
Barr Virus ◽  
Large B Cell Lymphoma ◽  
Programmed Death ◽  
Large B Cell

Abstract Introduction Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive malignancy commonly diagnosed in young adult females. In recent years, mutational and gene expression profiling has established genotypic and phenotypic similarity of PMBCL with both classical Hodgkin and diffuse large B-cell lymphoma (DLBCL). In-depth analyses of genomes and transcriptomes have highlighted several inactivating mutations (SOCS1, TP53), chromosomal amplifications (2p, 9p, Xp, Xq) and translocations (CIITA) thought to be integral in establishing and/or maintaining the PMBCL phenotype. Programmed death ligands (PDL) 1 (CD274) and 2 (PDCD1LG2), which are located on chromosome 9p24.1, are two emerging genes of interest that have been shown to be altered in PMBCL and can induce T-cell anergy by binding to the receptor, programmed death 1. Here, we describe the recurrence of chromosomal rearrangements of the PDL locus in various B-cell lymphomas and explore the association of these rearrangements with transcript levels. Methods To establish the frequency of CD274 and PDCD1LG2 aberration, we conducted fluorescence in situ hybridization (FISH) on 551 clinical samples and 20 established cell lines using in-house break-apart probes. Epstein-Barr virus encoded RNA in situ hybridization was also carried out on the clinical cohort. The clinical cases, sourced from the British Columbia Cancer Agency’s Centre for Lymphoid Cancer tissue repository, consisted of 125 PMBCLs, 216 DLBCLs, 130 primary DLBCL of the central nervous system (PCNSL), 12 nodular lymphocyte predominant Hodgkin lymphomas (NLPHL) and 68 follicular lymphomas (FL) with diagnoses based on the WHO classification. The DLBCL cohort could be further subdivided into 134 nodal DLBCLs and 82 testicular DLBCLs (T-DLBCL). Quantitative real-time PCR (qRT-PCR) was subsequently conducted on 17 cell lines and a clinical sub-cohort of 76 samples, for which fresh-frozen material was available, to determine the effect of mutations on transcript expression. We then characterized the PDL aberrations of two clinical PMBCL cases and three cell lines (DEV, L-428, L-1236), at base pair resolution, by applying the bioinformatic tools, nFuse, deFuse and destruct to both newly produced and previously published whole genome (WGS) and whole transcriptome (RNA-seq) libraries. Results FISH revealed a PDL locus (9p24.1) break-apart frequency of 20% (25/125) in PMBCL. There were no differences in any known clinical parameters or frequency of Epstein-Barr virus positivity between positive and negative PDL break-apart cases. Break-apart frequencies in other malignancies were calculated to be 3% in DLBCL, 7% in T-DLBCL and 1% in PCNSL; no positive cases were identified in either NLPHL or FL. The proportion of break-apart positive cases was significantly higher in PMBCL as compared to the other lymphomas surveyed (P < 0.05). Further, in agreement with the published literature, we observed an amplification frequency of the PDL locus in 36% (45/125) of PMBCLs. qRT-PCR established that PDCD1LG2 transcript levels were significantly higher in cases with 9p24.1 locus rearrangements compared to copy number neutral (P = 0.0003), gain (P = 0.001) and amplified cases (P = 0.005). Likewise, CD274 transcript levels were significantly higher in rearranged cases compared to copy number neutral cases (P = 0.03). Following the analysis of WGS and RNA-seq libraries, we were able to characterize four novel fusion transcripts involving the 9p24.1 locus: PDCD1LG2-NRG1 (PMBCL clinical case), PDCD1LG2-IGHV7-81 (L-1236), CIITA-PDCD1LG2 (DEV) and KIAA1432-CLDN14 (L-428). Aberrations involving both NRG1 and CIITA have previously been implicated in breast cancer and B-cell lymphomas, respectively. We also identified a translocation in another PMBCL clinical case with breakpoints in the intergenic spaces near LRMP and CD274, though this rearrangement did not produce a fusion transcript. Conclusion Taken together, our findings show that rearrangement of the PDL locus is recurrent in PMBCL, characteristic of PMBCL and leads to overexpression of PDL transcripts. Given the well-referenced function of PDLs in repressing the anti-tumor response, these data suggest that targeting the PDL axis in a subgroup of B-cell lymphomas holds clinical promise. Disclosures: No relevant conflicts of interest to declare.

scholarly journals PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

Blood ◽  
2018 ◽  
Vol 131 (1) ◽  
pp. 68-83 ◽  
Author(s):  
Zijun Y. Xu-Monette ◽  
Jianfeng Zhou ◽  
Ken H. Young
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
B Cell Lymphomas ◽  
Phase 2 Trial ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Programmed cell death protein 1 (PD-1) blockade targeting the PD-1 immune checkpoint has demonstrated unprecedented clinical efficacy in the treatment of advanced cancers including hematologic malignancies. This article reviews the landscape of PD-1/programmed death-ligand 1 (PD-L1) expression and current PD-1 blockade immunotherapy trials in B-cell lymphomas. Most notably, in relapsed/refractory classical Hodgkin lymphoma, which frequently has increased PD-1+ tumor-infiltrating T cells, 9p24.1 genetic alteration, and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORRs) of 65% to 87% and durable disease control in phase 1/2 clinical trials. The median duration of response was 16 months in a phase 2 trial. PD-1 blockade has also shown promise in a phase 1 trial of nivolumab in relapsed/refractory B-cell non-Hodgkin lymphomas, including follicular lymphoma, which often displays abundant PD-1 expression on intratumoral T cells, and diffuse large B-cell lymphoma, which variably expresses PD-1 and PD-L1. In primary mediastinal large B-cell lymphoma, which frequently has 9p24.1 alterations, the ORR was 35% in a phase 2 trial of pembrolizumab. In contrast, the ORR with pembrolizumab was 0% in relapsed chronic lymphocytic leukemia (CLL) and 44% in CLL with Richter transformation in a phase 2 trial. T cells from CLL patients have elevated PD-1 expression; CLL PD-1+ T cells can exhibit a pseudo-exhaustion or a replicative senescence phenotype. PD-1 expression was also found in marginal zone lymphoma but not in mantle cell lymphoma, although currently anti-PD-1 clinical trial data are not available. Mechanisms and predictive biomarkers for PD-1 blockade immunotherapy, treatment-related adverse events, hyperprogression, and combination therapies are discussed in the context of B-cell lymphomas.

Intraocular Lymphoma: Diagnostic Approach and Immunophenotypic Findings in Vitrectomy Specimens

2009 ◽  
Vol 133 (8) ◽  
pp. 1233-1237 ◽  
Author(s):  
Kirtee Raparia ◽  
Chung-Che(Jeff) Chang ◽  
Patricia Chévez-Barrios
Keyword(s):  
Flow Cytometry ◽  
B Cell ◽  
Who Classification ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intraocular Lymphoma ◽  
B Cell Lymphomas ◽  
Not Otherwise Specified ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractContext.—Diagnosis and classification of primary intraocular lymphoma can be challenging because of the sparse cellularity of the vitreous specimens.Objective.—To classify and clinically correlate intraocular lymphoma according to the World Health Organization (WHO) classification by using vitrectomy specimens.Design.—Clinical history, cytologic preparations, flow cytometry reports, and outcome of 16 patients diagnosed with intraocular lymphoma were reviewed.Results.—The study group included 10 women and 6 men. The mean age of the patients was 63 years (range, 19–79 years). Eleven patients had central nervous system involvement and 6 patients had systemic involvement. All cases were adequately diagnosed and classified according to the WHO classification by using combination of cytologic preparations and 4-color flow cytometry with a limited panel of antibodies to CD19, CD20, CD5, CD10, and κ and λ light chains. The cases included 9 primary diffuse large B-cell lymphomas of the CNS type; 2 diffuse large B-cell lymphomas, not otherwise specified; 1 extranodal, low-grade, marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT); 1 precursor B-lymphoblastic lymphoma; and 3 peripheral T-cell lymphomas, not otherwise specified. Of note, all 11 cases of diffuse large B-cell lymphoma were CD10−. All the patients received systemic chemotherapy and radiation therapy. Only 4 patients were free of disease at last follow-up (range, 18 months to 8 years), with severe visual loss.Conclusions.—Intraocular lymphoma cases can be adequately classified according to the WHO classification. Diffuse large B-cell lymphoma, CD10− and most likely of non–germinal center B-cell–like subgroup, is the most common subtype of non-Hodgkin lymphoma in this site, in contrast to ocular adnexal lymphoma for which MALT lymphoma is the most common subtype.

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