Cancer Research and Treatment

Original Articles

Hematologic malignancy

Predictive Parameters of Febrile Neutropenia and Clinical Significance of G-CSF Receptor Signaling Pathway in the Development of Neutropenia during R-CHOP Chemotherapy with Prophylactic Pegfilgrastim in Patients with Diffuse Large B-Cell Lymphoma: Do Young Kim, Jehyun Nam, Joo-Seop Chung, Byeol Eun Jeon, Ji Hyun Lee, Jae-Cheol Jo, Sang-Woo Kim, Ho-Jin Shin; Cancer Res Treat. 2022;54(4):1256-1267. Published online December 31, 2021; DOI: https://doi.org/10.4143/crt.2021.944

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Purpose
Pegfilgrastim is widely used to prevent chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) in patients with diffuse large B-cell lymphoma (DLBCL). We investigated the predictive factors affecting CIN and FN incidence in patients with DLBCL receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy with pegfilgrastim and conducted experiments to find reason for the occurrence of CIN even when pegfilgrastim was used.
Materials and Methods
We reviewed the CIN and FN events of 200 patients with DLBCL. Based on these data, we investigate the association with predictive factor and the levels of granulocyte-colony stimulating factor (G-CSF) receptor signaling pathway markers (pSTAT3, pAKT, pERK1/2, pBAD, and CXCR4) in bone marrow (BM) samples isolated from patients with DLBCL.
Results
FN was significantly associated with stage III/IV (hazard ratio [HR], 12.74) and low serum albumin levels (HR, 3.87). Additionally, patients with FN had lower progression-free survival (PFS; 2-year PFS, 51.1 % vs. 74.0%) and overall survival (OS; 2-year OS, 58.2% vs. 85.0%) compared to those without FN. The occurrence of CIN was associated with overexpression of G-CSF receptor signaling pathway markers, and expression levels of these markers were upregulated in BM cells co-cultured with DLBCL cells. The rate of neutrophil apoptosis was also higher in neutrophils co-cultured with DLBCL cells and was further promoted by treatment with doxorubicin.
Conclusion
Our findings suggest that high DLBCL burden may alter the BM environment and G-CSF receptor signaling pathway, even in chemotherapy-naïve state, which may increase CIN frequency during R-CHOP chemotherapy.

Citations

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Hypogammaglobulinemia at Diagnosis is Associated With Inferior Survival and Higher Risk of Infections in Diffuse Large B Cell Lymphoma
Åsa Lindberg, Åsa Johansson, Fredrik Kahn, Göran Jönsson, Mats Jerkeman
Hematological Oncology.2025;[Epub] CrossRef
Sarcopenia attenuates the efficacy of PEGylated granulocyte colony-stimulating factor in preventing febrile neutropenia
Se-Il Go, Eun-Jeong Jeong, Woo Je Lee, Sungwoo Park, Mi Jung Park, Gyeong-Won Lee
Supportive Care in Cancer.2025;[Epub] CrossRef
Predictive Model for Occurrence of Febrile Neutropenia after Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma: A Multicenter, Retrospective, Observational Study
Masaya Morimoto, Yuma Yokoya, Kikuaki Yoshida, Hideki Kosako, Yoshikazu Hori, Toshiki Mushino, Shinobu Tamura, Reiko Ito, Ryosuke Koyamada, Takuya Yamashita, Shinichiro Mori, Nobuyoshi Mori, Sachiko Ohde
Hematology Reports.2024; 16(1): 76. CrossRef
Multi‐omics integration reveals the oncogenic role of eccDNAs in diffuse large B‐cell lymphoma through STING signalling
Zijuan Wu, Wei Zhang, Luqiao Wang, Jiayan Leng, Yongle Li, Zhou Fan, Mengtao Zhan, Lei Cao, Yongning Jiang, Yan Jiang, Bing Sun, Jianxin Fu, Jianyong Li, Wenyu Shi, Hui Jin
Clinical and Translational Medicine.2024;[Epub] CrossRef
Transcriptomic analysis of neutrophil apoptosis induced by diffuse large B-cell lymphoma unveils a potential role in neutropenia
Byeol-Eun Jeon, Ji-Eun Lee, Jungwook Park, Hyejung Jung, Eun Gyung Park, Du Hyeong Lee, Young-Su Seo, Heui-Soo Kim, Ho-Jin Shin, Sang-Woo Kim
Genes & Genomics.2023; 45(8): 1013. CrossRef

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Role of Roflumilast Combined with ESHAP Chemotherapy in Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma: Do Young Kim, Jehyun Nam, Joo-seop Chung, Sang-Woo Kim, Ho-Jin Shin; Cancer Res Treat. 2022;54(1):301-313. Published online April 27, 2021; DOI: https://doi.org/10.4143/crt.2020.1371

Abstract PDF PubReader ePub

Purpose
There are unmet needs associated with the current treatment strategies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) due to the poor treatment outcomes of these strategies. Roflumilast, a selective phosphodiesterase-4 inhibitor used for treating chronic obstructive pulmonary disease, is effective against B-cell malignancy via phosphoinositide 3-kinase (PI3K)–activity suppression. We analyzed the effects of roflumilast combined with ESHAP (etoposide, cisplatin, methylprednisolone, and cytarabine) chemotherapy in experimental and clinical settings.
Materials and Methods
An in vitro study using lymphoma cell lines and a pilot study on relapsed/refractory DLBCL patients were conducted to investigate the effects and mechanism of the combination of roflumilast and chemotherapy. The complete response (CR), overall response rate (ORR), and 1-year progression-free survival (PFS) were analyzed.
Results
We found that roflumilast is efficient when combined with other chemotherapy drugs, especially cytarabine. Synergistic effects between these two drugs influence the translation of mammalian target of rapamycin and myeloid cell leukemia 1, resulting in apoptosis and inhibition of B-cell lymphoma proliferation. In clinical setting, the roflumilast group showed better rates of CR (46.2% vs. 34.6%), ORR (76.9% vs. 53.8%), and 1-year PFS (50.0% vs. 25.9%) compared with the control group, though not statistically significant. The roflumilast group showed a higher incidence of asthenia and gastrointestinal adverse events. However, grade 3 or 4 adverse events were similar in both groups.
Conclusion
We found that roflumilast, when combined with ESHAP chemotherapy, for relapsed/refractory DLBCL was clinically active and well tolerated. This combined treatment was able to suppress PI3K activity, which is correlated with the degree of clinical response.

Citations

Citations to this article as recorded by

Metastasis-Associated Wound Repair Promotes Reciprocal Lung Epithelium Activation and Breast Cancer Metastatic Outgrowth
Jessica L. Christenson, Nicole S. Spoelstra, Michelle M. Williams, Linda L. Logan, Kathleen I. O’Neill, David J. Orlicky, Nolan T. Baker, Jennifer A. Wagner, Alyse W. Staley, Adrie Van Bokhoven, Andrew Goodspeed, Li-Wei Kuo, Lyndsey S. Crump, Jennifer R.
Cancer Research Communications.2026; 6(4): 750. CrossRef
Roflumilast attenuates doxorubicin and cyclophosphamide combination-induced chemobrain in rats through modulation of NLRP3/ASC/caspase-1/GSDMD axis
Georgette Eskander, Sherihan G. Abdelhamid, Sara A. Wahdan, Sara M. Radwan
Life Sciences.2025; 362: 123378. CrossRef
The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy
Huili-li Ren, Shao-hui Zhang, Pei-yuan Li
Frontiers in Immunology.2025;[Epub] CrossRef
Roflumilast tópico y oral en dermatología. Una revisión narrativa
M. Mansilla-Polo, E. Gimeno, D. Morgado-Carrasco
Actas Dermo-Sifiliográficas.2024; 115(3): 265. CrossRef
cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment
Hongying Zhang, Yongliang Liu, Jieya Liu, Jinzhu Chen, Jiao Wang, Hui Hua, Yangfu Jiang
Journal of Hematology & Oncology.2024;[Epub] CrossRef
[Translated aticle] Topical and Oral Roflumilast in Dermatology: A Narrative Review
M. Mansilla-Polo, E. Gimeno, D. Morgado-Carrasco
Actas Dermo-Sifiliográficas.2024; 115(3): T265. CrossRef
Advances in diagnosis, treatment and prognostic factors of gastrointestinal DLBCL
Qinqiao Lai, Yan Zhao, Haiqing Yan, Hongling Peng
Leukemia Research.2023; 135: 107406. CrossRef

9,320 View
223 Download
6 Web of Science
7 Crossref

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