Morphologic heterogeneity is only part of the picture for patients with high‐grade B‐cell lymphomas, and many of these lymphomas are biologically driven by equally complex variations in genetics and ...protein expression. In this patient population, novel targeted therapies need to be tested in combination with chemoimmunotherapy in the front‐line setting, because the proportion of patients who progress early is so high, and many patients do not appear to be salvageable with further conventional chemotherapy regimens.
Purpose: In B-cell chronic lymphocytic leukemia (CLL), high CD38 expression has been associated with unfavorable clinical course,
advanced disease, resistance to therapy, shorter time to first ...treatment, and shorter survival. However, the genes associated
with CLL patient subgroups with high and low CD38 expression and their potential role in disease progression is not known.
Experimental Design: To identify the genes associated with the clinical disparity in CLL patients with high versus low CD38 expression, transcriptional
profiles were obtained from CLL cells from 39 different patients using oligonucleotide microarray. Gene expression was also
compared between CLL cells and B cells from healthy individuals.
Results: Gene expression analysis identified 76 differentially expressed genes in CD38 high versus low groups. Out of these genes,
HEM1, CTLA4 , and MNDA were selected for further studies and their differential expression was confirmed by real-time PCR. HEM1 overexpression was
associated with poor outcome, whereas the overexpression of CTLA4 and MNDA was associated with good outcome. Down-regulation
of HEM1 expression in patient CLL cells resulted in a significant increase in their susceptibility to fludarabine-mediated
killing. In addition, when gene expression patterns in CD38 high and low CLL cells were compared with normal B-cell profiles,
ATM expression was found to be significantly lower in CD38 high compared with CD38 low CLL as confirmed by real-time reverse
transcription-PCR.
Conclusions: These results identify the possible genes that may be involved in cell proliferation and survival and, thus, determining
the clinical behavior of CLL patients expressing high or low CD38.
Health disparities exist according to an individual's place of residence. We evaluated the association between primary area of residence (urban v rural) according to treatment provider (university ...based v community based) and overall survival in patients with lymphoma and determined whether there are patient groups that could benefit from better coordination of care.
Population-based, retrospective cohort study of 2,330 patients with centrally confirmed lymphoma from Nebraska and surrounding states and treated by university-based or community-based oncologists from 1982 to 2006.
Among urban residents, 321 (14%) were treated by university-based providers (UUB) and 816 (35%) were treated by community-based providers (UCB). Among rural residents, 332 (14%) were treated by university-based providers (RUB), and 861 (37%) were treated by community-based providers (RCB). The relative risk (RR) of death among UUB, UCB, and RUB were not statistically different. However, RCB had a higher risk of death (RR, 1.37; 95% CI, 1.14 to 1.65; P = .01; and RR, 1.26; 95% CI, 1.06 to 1.49; P = .01) when compared with UUB and RUB, respectively. This association was true in both low- and intermediate-risk patients. Among high-risk patients, UCB, RUB, and RCB were all at higher risk of death when compared with UUB.
Survival outcomes of patients with lymphoma may be associated with place of residence and treatment provider. High-risk patients from rural areas may benefit from better coordination of care.
Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling ...and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli.
SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL.
The article by Thieblemont C and colleagues very nicely summarizes the key pathogenetic and diagnostic features and present treatment of splenic marginal zone lymphoma (SMZL). This histologic subtype ...of nonHodgkin lymphoma has evolved from being an unrecognized entity in earlier classification systems (such as the Working Formulationfl), to a provisional entity in the Revised Europe an/ American Lymphoma (REAL) classification, 2 and finally to a fully recognized distinct clinicopathologic entity in the World Health Organization (WHO) classification system. 3 The WHO classification system separates marginal zone B-cell lymphomas into three clinically distinct subtypes: nodal marginal zone lymphomas, extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas), and SMZL. Although SMZL accounts for only approximately 2% of non-Hodgkin lymphomas.4 it is associated with unique features that continue to build a case for an infectious/chronic inflammatory etiology in at least a percentage of patients. Although a single distinct pathway elucidating the pathogenesis of marginal zone lymphomas has not emerged, some data suggest that the cells are memory B lymphocytes, since they arise from cells in the marginal zone of secondary lymphoid follicles. In a relatively large percentage of cases, the malignant cells appear to have undergone somatic hyp er mutation (ie, are of post-germinal center origin), implying the presence of previous antigenic exposure. However, other data suggest the possibility that the cell of origin may be a circulating B cell that has undergone somatic hypermutation independent of the germinal center mechanism and is pre- antigen- exposed. 5 Marginal zone lymphomas are frequently associated with the presence of chronic antigenic stimulation - either infectious antigens or possibly host auto- antigens. SMZL has frequently been associated with the presence of antibodies to hepatitis C virus (HCV). 6 The presence of a transmembrane protein known as CD81 on the surface of these B cells may provide a pathway through which HCV can cause B-cell activation via the B-cell receptor. 7 Patients with SMZL may present with manifestations of autoimmune disease (eg, autoimmune hemolytic anemia/thrombocytopenia, antiphospholipid antibody syndrome) or manifestations of HCV infection (eg, cryoglobulinemia). 8,9 It appears that patients with either a monoclonal protein or immunologic manifestations of their disease may have shorter remissions than those whose disease does not have these features. 10
Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic ...lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eμ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.
Philadelphia chromosome-positive acute myeloid leukemia (Ph(+)-AML) has a poor response to anthracycline- and cytarabine-containing regimens, high relapse rate, and dismal prognosis. Although therapy ...with imatinib and allogeneic stem cell transplantation (allo-SCT) is promising, relatively short follow-up limits understanding of long-term results of these therapies. This report describes the outcomes of 3 cases of Ph(+)-AML diagnosed and transplanted at the University of Nebraska Medical Center between 2004 and 2011. These patients, young and without major comorbidities, received induction therapy with 7 days of cytarabine and 3 days of idarubicin along with imatinib and consolidation therapy with high-dose cytarabine (with or without imatinib). All patients underwent 10/10 HLA-matched peripheral blood allo-SCT (sibling donor for first and third patients and unrelated donor for the second patient; all had acute graft-versus-host disease (GVHD), and the first and third patients had chronic GVHD. All patients are currently alive and experiencing complete remission at 116, 113, and 28 months after diagnosis, respectively. This report shows that the use of allo-SCT with resultant graft-versus-leukemia effect and the addition of imatinib can result in long-term remission and possible cure in some patients with Ph(+)-AML.
The objective of this retrospective study (N = 169) was to compare the overall survival (OS) of different subtypes of mantle cell lymphoma (MCL) treated by the Nebraska Lymphoma Study Group between ...1984 and 2012. The overall response rate to various therapies including stem cell transplant (SCT) was similar (p = 0.44) between blastoid, diffuse and nodular subtypes. At 5 years, blastoid and diffuse subtypes had worse OS (overall p = 0.005) compared to nodular subtype. In multivariate analysis, the blastoid and diffuse subtypes had similar risk of death (p = 0.14) whereas the nodular subtype had a lower risk compared to blastoid (HR 0.48, 95% CI 0.27-0.87, p = 0.01). The use of SCT was associated with lower risk of death. In univariate analysis, blastoid subtype had better OS with intensive upfront therapy. In conclusion, the OS of blastoid subtype is worse than nodular MCL but may improve with the use of SCT and probably intensive induction therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This large population-based study determined the epidemiology and outcomes of secondary acute myeloid leukemia (sAML) developing in Hodgkin lymphoma survivors.
We utilized the Surveillance ...Epidemiology and End Results (SEER) 9 database to identify 104 cases of sAML.
Patients with sAML (median age: 47 years; 82% <60 years) were significantly younger than de novo AML cases (66 years; p < 0.01). sAML had worse overall survival (OS) than de novo AML (p < 0.01). OS was better in younger patients and in more recent years.
Older patients with sAML have a dismal OS and should be enrolled in trials of novel therapies. Younger patients have improved OS and hence may benefit from curative intent intensive therapy and allogeneic transplant.
Structured Abstract Background Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare entity with no prior population-based study. Methods We used the Surveillance, Epidemiology and End ...Results (SEER) 18 database to identify adult patients with SPTCL and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) diagnosed between 1973 and 2011. The actuarial survival of SPTCL was compared to a propensity matched cohort of PTCL, NOS. Multivariate analysis was conducted using weighted Cox proportional hazard regression model. Results Patients with SPTCL (n = 118), compared to PTCL, NOS (n = 3296), were more likely to be younger (median age of 47 vs. 62 years, p < 0.01), women (67 % vs 40%, p < 0.01) and diagnosed with stage I/II disease (46% vs. 36%, p = 0.01). The five year actuarial, relative and cause specific survival for SPTCL was 40%, 57% and 64% respectively. After propensity matching, the 5-year overall survival (OS) of SPTCL was better than that of PTCL, NOS (57% vs. 40%. p < 0.01). In a multivariate analysis, mortality was significantly lower among SPTCL vs. PTCL, NOS (hazard ratio, HR 0.54; 95% CI 0.39-0.75; p < 0.01). Among patients with SPTCL, advanced age (p < 0.01) and diagnosis before the year 2008 (p 0.02) were predictors of worse OS. Conclusions Our study provides characteristics and OS of a large cohort of SPTCL. As compared to PTCL, NOS, SPTCL patients were more likely to be younger, females and diagnosed at an early stage. The OS of SPTCL was better than PTCL, NOS.
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