Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure

Hu, Jingtian; Wang, Xin; Chen, Fei; Ding, Mengjie; Meng, Di; Yang, Wenbo; Yin, Meifeng; Wu, Jingjing; Zhang, Lei; Fu, Xiaorui; Sun, Zhenchang; Li, Ling; Wang, Xinhua; Li, Xin; Guo, Shuang; Zhang, Dianbao; Lü, Xiaohui; Leng, Qing; Zhang, Mingzhi; Zhu, Linan; Zhang, Xudong; Chen, Qingjiang

doi:10.3389/fonc.2021.687374

Cited by 11 publications

(11 citation statements)

References 41 publications

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“…For the cell line with the most pronounced response to Dexamethasone treatment, OCI-LY1, the in vitro findings could also be recapitulated in the corresponding in vivo xenograft model. This confirms that at least the corticosteroid component of stabilizing chemotherapy regimens in DLBCL patients [ 8 , 9 ] prior to CXCR4-targeted RLT with [ 177 Lu]Lu-PentixaTher does not lead to downregulation of the molecular target CXCR4 and may even have a contrary, beneficiary effect. However, it needs to be investigated in more detail to which extent rituximab or the other chemotherapeutic agents used in CHOP or DHAP treatment protocols affect CXCR4 expression, since these effects may limit the use of CXCR4-targeted diagnostics and/or CXCR4-targeted therapies [ 4 ].…”

Section: Resultssupporting

confidence: 63%

“…Clinically, in the management of DLBCL, the combination of CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone a ) and rituximab is considered a standard first-line treatment [ 8 ], whereas modified/extended DHAP (Dexamethasone, Cytarabine, Cisplatin) protocols are used as second-line chemotherapies [ 9 ]. Since patients with DLBCL eligible for [ 177 Lu]Lu/[ 90 Y]Y-PentixaTher RLT are very likely to undergo/have undergone one of these treatments, Prednisolone 1 and Dexamethasone were both included into this investigation.…”

Section: Background and Study Designmentioning

confidence: 99%

“…To ensure the reliability of the in vitro data, the concentrations for Dexamethasone and Prednisolone were chosen such as to resemble as closely as possible to the maximum plasma concentrations observed in humans receiving standard treatments (i.e., 40 mg Dexamethasone/day [ 9 ] and 100 mg Prednisone/day [ 8 ]). On the basis of this dosing, the corresponding maximum plasma concentrations for Dexamethasone and Prednisolone were found to be approximately 0.5 µM [ 10 ] and 5 µM [ 11 ], respectively.…”

Section: Background and Study Designmentioning

confidence: 99%

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Influence of corticosteroid treatment on CXCR4 expression in DLBCL

Martin

Viertl

Janz³

et al. 2023

EJNMMI Res

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Background CXCR4-targeted radioligand therapy (RLT) with [177Lu]Lu/[90Y]Y-PentixaTher has recently evolved as a promising therapeutic option for patients with advanced hematological cancers. Given their advanced disease stage, most patients scheduled for PentixaTher RLT require concomitant or bridging chemotherapy to prevent intermittent tumor progression. These (mostly combination) therapies may cause significant downregulation of tumoral CXCR4 expression, challenging the applicability of PentixaTher RLT. This study therefore aimed at investigating the influence of corticosteroids, a central component of these chemotherapies, on CXCR4 regulation in diffuse large B cell lymphoma (DLBCL). Methods Different DLBCL cell lines (Daudi, OCI-LY1, SUDHL-4, -5-, -6 and -8) as well as the human T-cell lymphoma cell line Jurkat were incubated with Dexamethasone (Dex; 0.5 and 5 µM, respectively) and Prednisolone (Pred; 5 and 50 µM, respectively) for different time points (2 h, 24 h). Treatment-induced modulation of cellular CXCR4 surface expression was assessed via flow cytometry (FC) and compared to untreated cells. A radioligand binding assay with [125I]CPCR4.3 was performed in parallel using the same cells. To quantify potential corticosteroid treatment effects on tumoral CXCR4 expression in vivo, OCI-LY1 bearing NSG mice were injected 50 µg Dex/mouse i.p. (daily for 6 days). Then, a biodistribution study (1 h p.i.) using [68Ga]PentixaTher was performed, and tracer biodistribution in treated (n = 5) vs untreated mice (n = 5) was compared. Results In the in vitro experiments, a strongly cell line-dependent upregulation of CXCR4 was observed for both Dex and Pred treatment, with negligible differences between the high and low dose. While in Jurkat, Daudi and SUDHL-8 cells, CXCR4 expression remained unchanged, a 1.5- to 3.5-fold increase in CXCR4 cell surface expression was observed for SUDHL-5 < SUDHL-4 /-6 < OCI-LY1 via FC compared to untreated cells. This increase in CXCR4 expression was also reflected in correspondingly enhanced [125I]CPCR4.3 accumulation in treated cells, with a linear correlation between FC and radioligand binding data. In vivo, Dex treatment led to a general increase of [68Ga]PentixaTher uptake in all organs compared to untreated animals, as a result of a higher tracer concentration in blood. However, we observed an overproportionally enhanced [68Ga]PentixaTher uptake in the OCI-LY1 tumors in treated (21.0 ± 5.5%iD/g) vs untreated (9.2 ± 2.8%iD/g) mice, resulting in higher tumor-to-background ratios in the treatment group. Conclusion Overall, corticosteroid treatment (Dex/Pred) consistently induced an upregulation of CXCR4 expression DBLCL cells in vitro, albeit in a very cell line-dependent manner. For the cell line with the most pronounced Dex-induced CXCR4 upregulation, OCI-LY1, the in vitro findings were corroborated by an in vivo biodistribution study. This confirms that at least the corticosteroid component of stabilizing chemotherapy regimens in DLBCL patients prior to [177Lu]Lu-PentixaTher RLT does not lead to downregulation of the molecular target CXCR4 and may even have a beneficiary effect. However, further studies are needed to investigate if and to what extent the other commonly used chemotherapeutic agents affect CXCR4 expression on DLBCL to ensure the choice of an appropriate treatment regimen prior to [177Lu]Lu/[90Y]Y-PentixaTher RLT.

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Section: Resultssupporting

confidence: 63%

Section: Background and Study Designmentioning

confidence: 99%

Section: Background and Study Designmentioning

confidence: 99%

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Influence of corticosteroid treatment on CXCR4 expression in DLBCL

Martin

Viertl

Janz³

et al. 2023

EJNMMI Res

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“…It displays cytotoxicity at high concentrations, whereas low doses can minimize toxicity and may improve the targeting effect of DNA hypomethylation through a re-expression of tumor suppressor genes during tumor therapy (133). A phase 4 clinical trial investigated the efficacy of a combination of decitabine together with a modified regimen of cisplatin, cytarabine, and dexamethasone (DHAP) in relapsed/refractory DLBCL (r/r DLBCL) (134). The results showed that overall response rate (ORR) reached 50% and complete response rate (CRR) reached 35%.…”

Section: Dnmt Inhibitors 2211 Decitabinementioning

confidence: 99%

The Status and Prospects of Epigenetics in the Treatment of Lymphoma

Liu

et al. 2022

Front. Oncol.

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The regulation of gene transcription by epigenetic modifications is closely related to many important life processes and is a hot research topic in the post-genomic era. Since the emergence of international epigenetic research in the 1990s, scientists have identified a variety of chromatin-modifying enzymes and recognition factors, and have systematically investigated their three-dimensional structures, substrate specificity, and mechanisms of enzyme activity regulation. Studies of the human tumor genome have revealed the close association of epigenetic factors with various malignancies, and we have focused more on mutations in epigenetically related regulatory enzymes and regulatory recognition factors in lymphomas. A number of studies have shown that epigenetic alterations are indeed widespread in the development and progression of lymphoma and understanding these mechanisms can help guide clinical efforts. In contrast to chemotherapy which induces cytotoxicity, epigenetic therapy has the potential to affect multiple cellular processes simultaneously, by reprogramming cells to achieve a therapeutic effect in lymphoma. Epigenetic monotherapy has shown promising results in previous clinical trials, and several epigenetic agents have been approved for use in the treatment of lymphoma. In addition, epigenetic therapies in combination with chemotherapy and/or immunotherapy have been used in various clinical trials. In this review, we present several important epigenetic modalities of regulation associated with lymphoma, summarize the corresponding epigenetic drugs in lymphoma, and look at the future of epigenetic therapies in lymphoma.

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“…follicular lymphoma and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), or aggressive subtypes, such as diffuse large B-cell lymphoma (DLCBL) and Burkitt lymphoma (BL) [12,13]. The standard rst-line therapy for aggressive lymphomas, based upon polychemotherapy plus the anti-CD20 antibody rituximab, yields about 60% of responders [14,15]; however, for patients who do not respond to rst-line therapies and failed second options, representing about the 30-40% of cases, treatment outcomes are very poor [16,17].…”

mentioning

confidence: 99%

Targeted chitosan nanobubbles as a strategy to down-regulate microRNA-17 into B-cell lymphoma models

Capolla

Argenziano

D'Agaro

et al. 2022

Preprint

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Background: MicroRNAs represent interesting targets for new therapies because their altered expression influences tumor development and progression. miR-17 is a prototype of onco-miRNA, known to be overexpressed in B-cell non-Hodgkin lymphoma (B-NHL) with peculiar clinic-biological features. AntagomiR molecules have been largely studied to repress the regulatory functions of up-regulated onco-miRNAs, but their clinical use is mainly limited by their rapid degradation, kidney elimination and poor cellular uptake when injected as naked oligonucleotides. To overcome these problems, we exploited CD20 targeted chitosan nanobubbles (NBs) for a preferential and safe delivery of antagomiR17 to B-NHL cells. Results: Positively charged 400 nm-sized nanobubbles (NBs) represent a stable and effective nanoplatform for antagomiR encapsulation and specific release into B-NHL cells. NBs rapidly accumulated in tumor microenvironment, but only those conjugated with a targeting system (antiCD20 antibodies) were internalized into B-NHL cells, releasing antagomiR17 in the cytoplasm, both in vitro and in vivo. The result is the down-regulation of miR-17 level and the reduction in tumor burden in a human-mouse B-NHL model, without any documented side effects. Conclusions: Anti-CD20 targeted NBs investigated in this study showed physico-chemical and stability properties suitable for antagomiR17 delivery in vivo and represent a useful nanoplatform to address B-cell malignancies or other cancers through the modification of their surface with specific targeting antibodies.

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Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure

Cited by 11 publications

References 41 publications

Influence of corticosteroid treatment on CXCR4 expression in DLBCL

Influence of corticosteroid treatment on CXCR4 expression in DLBCL

The Status and Prospects of Epigenetics in the Treatment of Lymphoma

Targeted chitosan nanobubbles as a strategy to down-regulate microRNA-17 into B-cell lymphoma models

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