Role of Roflumilast Combined with ESHAP Chemotherapy in Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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.
Abstract
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.
참고문헌 (30)
- 이혜원, "Nationwide Statistical Analysis of Lymphoid Malignancies in Korea", Cancer Research and Treatment, 50(1), pp.222~238 (2018), 대한암학회
- Martelli M, "Diffuse large B-cell lymphoma", Crit Rev Oncol Hematol, 87, pp.146~171 (2013)
- Coiffier B, "CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma", N Engl J Med, 346, pp.235~242 (2002)
- Philip T, "High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin’s lymphoma", N Engl J Med, 316, pp.1493~1498 (1987)
- Crump M, "Outcomes in refractory diffuse large B-cell lymphoma : results from the international SCHOLAR-1 study", Blood, 130, pp.1800~1808 (2017)
- Gisselbrecht C, "Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era", J Clin Oncol, 28, pp.4184~4190 (2010)
- National Comprehensive Cancer Network, "NCCN guidelines for diffuse large B-cell lymphoma", National Comprehensive Cancer Network, ~ (2020)
- Wedzicha JA, "Roflumilast : a review of its use in the treatment of COPD", Int J Chron Obstruct Pulmon Dis, 11, pp.81~90 (2016)
- Smith PG, "The phosphodiesterase PDE4B limits cAMP-associated PI3K", AKT-dependent apoptosis in diffuse large B-cell lymphoma, 2005, pp.105, 308~316
- Suhasini AN, "A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma", Leukemia, 30, pp.617~626 (2016)
- Bosnjak M, "Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death", PLoS One, 9, pp.e94374~ (2014)
- Kim SW, "Gene set enrichment analysis unveils the mechanism for the phosphodiesterase 4B control of glucocorticoid response in B-cell lymphoma", Clin Cancer Res, 17, pp.6723~6732 (2011)
- Schuster SJ, "Primary analysis of juliet : a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma", Blood, 130(Suppl 1), pp.577~ (2017)
- Sehn LH, "Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma", J Clin Oncol, 38, pp.155~165 (2020)
- Viardot A, "Phase 2 study of the bispecific T-cell engager(BiTE)antibody blinatumomab in relapsed", refractory diffuse large B-cell lymphoma, 2016, pp.127, 1410~1416
- Sunahara RK, "Isoforms of mammalian adenylyl cyclase : multiplicities of signaling", Mol Interv, 2, pp.168~184 (2002)
- Bender AT, "Cyclic nucleotide phosphodiesterases : molecular regulation to clinical use", Pharmacol Rev, 58, pp.488~520 (2006)
- Shipp MA, "Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning", Nat Med, 8, pp.68~74 (2002)
- Lossos IS, "Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes", N Engl J Med, 350, pp.1828~1837 (2004)
- Zhao S, "Machine learning-based classification of diffuse large B-cell lymphoma patients by eight gene expression profiles", Cancer Med, 5, pp.837~852 (2016)
- Zhao KH, "Antiglioma effects of cytarabine on leptomeningeal metastasis of high-grade glioma by targeting the PI3K", Akt, Drug Des Devel Ther, pp.2017, 11[DOI]
- Galmarini CM, "Pyrimidine nucleoside analogs in cancer treatment", Expert Rev Anticancer Ther, 3, pp.717~728 (2003)
- Velasquez WS, "ESHAP : an effective chemotherapy regimen in refractory and relapsing lymphoma : a 4-year follow-up study", J Clin Oncol, 12, pp.1169~1176 (1994)
- Ezzat AA, "E-SHAP : an effective treatment in selected patients with relapsed non-Hodgkin’s lymphoma", Ann Oncol, 5, pp.453~456 (1994)
- ChulWonChoi, "ESHAP Salvage Therapy for Relapsed or Refractory Non-Hodgkin's Lymphoma", Journal of Korean Medical Science, 17(5), pp.621~624 (2002), 대한의학회
- Martin A, "R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL", TAMO study, 2008, pp.93, 1829~1836
- Kim DU, "Phosphodiesterase 4B is an effective therapeutic target in colorectal cancer", Biochem Biophys Res Commun, 508, pp.825~831 (2019)
- Domvri K, "Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer", J Cancer, 8, pp.3648~3656 (2017)
- Kelly K, "Safety and pharmacodynamics of the PDE4 inhibitor roflumilast in advanced B-cell malignancies", Clin Cancer Res, 23, pp.1186~1192 (2017)
- Cooney JD, "Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies", Blood, 128, pp.2886~2890 (2016)