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K. Miyazaki et al.
that in previous reports (36-37%).17,18,28 However, the inci- dence of FN per cycle of DA-EPOCH in our study was 23%, which was comparable to that in previous reports for DA-EPOCH-R (19%).17,40 The long period (7 months) of this protocol treatment may have resulted in the high pro- portion of patients who experienced FN. All patients with FN promptly recovered after initial antibiotic therapy and had no serious events. Hence, the toxicity could be consid- ered manageable. Although secondary malignancy was observed in three patients, all of them were older, and two of them were treated with salvage chemotherapy after relapse. A longer follow up is needed to adequately evalu- ate second malignancies.
Our study has several limitations. First, it is a non-ran- domized phase II study with a small number of patients. Second, 96% of the patients had good PS (< 2). Third, the follow-up period for the evaluation of secondary malig- nancy was short. Fourth, considering the rarity of the dis- ease and the feasibility of the clinical trial, this study was not designed to assess 2-year CNS relapse rate as a pri- mary end point. Nevertheless, our results showed promis-
ing efficacy and manageable toxicity of DA-EPOCH- R/HD-MTX for untreated stage II-IV CD5+ DLBCL, and this trial is an important initial step in developing a more effective treatment strategy. To assess long-term efficacy and toxicity including second malignancy, a 5-year follow up is scheduled in November 2020.
Acknowledgments
We would like to thank all of the patients, hemato-oncologists, and pathologists at the participating institutes for invaluable con- tributions to this multicenter study.
Funding
This study was supported by grants-in-aid from the Japan Agency for Medical Research and Development, AMED (the Practical Research for Innovative Cancer Control; JP15Ack0106157, JP16ck0106157, JP17ck0106157, JP18ck0106439), the Ministry of Labour, Health, and Welfare of Japan (201438142A), the director of Mie University Hospital (2012, 2013), and the National Cancer Center Research and Development Fund (26-A-4, 29-A-3).
References
1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC Press, 2008.
2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon: IARC Press, 2017.
3. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict sur- vival after chemotherapy for diffuse large-B- cell lymphoma. N Engl J Med. 2002; 346(25):1937-1947.
4. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313-2323.
5. Yamaguchi M, Seto M, Okamoto M, et al. De novo CD5+ diffuse large B-cell lym- phoma: a clinicopathologic study of 109 patients. Blood. 2002;99(3):815-821.
6. YamaguchiM,NakamuraN,SuzukiR,etal. De novo CD5+ diffuse large B-cell lym- phoma: results of a detailed clinicopatholog- ical review in 120 patients. Haematologica. 2008;93(8):1195-1202.
7. Ennishi D, Takeuchi K, Yokoyama M, et al. CD5 expression is potentially predictive of poor outcome among biomarkers in patients with diffuse large B-cell lymphoma receiv- ing rituximab plus CHOP therapy. Ann Oncol. 2008;19(11):1921-1926.
8. Miyazaki K, Yamaguchi M, Suzuki R, et al. CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without ritux- imab. Ann Oncol. 2011;22(7):1601-1607.
9. Xu-Monette ZY, Tu M, Jabbar KJ, et al. Clinical and biological significance of de novo CD5+ diffuse large B-cell lymphoma in Western countries. Oncotarget. 2015; 6(8):5615-5633.
10. Alinari L, Gru A, Quinion C, et al. De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter,
11.
12.
13.
14.
15.
16.
17.
18.
19. 20.
rituximab treated cohort. Am J Hematol. 2016;91(4):395-399.
Hyo R, Tomita N, Takeuchi K, et al. The therapeutic effect of rituximab on CD5-pos- itive and CD5-negative diffuse large B-cell lymphoma. Hematol Oncol. 2010;28(1):27- 32.
Johnson NA, Boyle M, Bashashati A, et al. Diffuse large B-cell lymphoma: reduced CD20 expression is associated with an infe- rior survival. Blood. 2009;113(16):3773- 3780.
Salles G, de Jong D, Xie W, et al. Prognostic significance of immunohistochemical bio- markers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium. Blood. 2011; 117(26):7070-7078.
Chuang WY, Chang H, Shih LY, et al. CD5 positivity is an independent adverse prog- nostic factor in elderly patients with diffuse large B cell lymphoma. Virchows Arch. 2015;467(5):571-582.
Suguro M, Tagawa H, Kagami Y, et al. Expression profiling analysis of the CD5+ diffuse large B-cell lymphoma subgroup: development of a CD5 signature. Cancer Sci. 2006;97(9):868-874.
Miyazaki K, Yamaguchi M, Imai H, et al. Gene expression profiling of diffuse large B- Cell lymphomas supervised by CD5 expres- sion. Int J Hematol. 2015;102(2):188-194. Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008;26(16):2717-2724.
Wilson WH, Jung SH, Porcu P, et al. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012;97(5):758-765. Grommes C, DeAngelis LM. Primary CNS Lymphoma. J Clin Oncol. 2017;35(21):2410- 2418.
Miyazaki K, Yamaguchi M, Umino A, et al. DA-EPOCH-R Combined With High-dose
Methotrexate For Newly Diagnosed CD5- positive Diffuse Large B-cell Lymphoma. Hematol Oncol. 2013;31:227.
21. Feugier P, Van Hoof A, Sebban C, et al. Long- term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005;23(18):4117- 4126.
22. Wilson WH, Grossbard ML, Pittaluga S, et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a phar- macodynamic approach with high efficacy. Blood. 2002;99(8):2685-2693.
23. A predictive model for aggressive non- Hodgkin's lymphoma. N Engl J Med. 1993; 329(14):987-994.
24. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classifica- tion of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282.
25. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of dif- fuse large B-cell lymphoma using gene expression in formalin-fixed paraffin- embedded tissue. Blood. 2014;123(8):1214- 1217.
26. Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: a risk model for CNS relapse in patients with dif- fuse large B-cell lymphoma treated with R- CHOP. J Clin Oncol. 2016;34(26):3150-3156.
27. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lym- phoma. J Clin Oncol. 2007;25(5):579-586.
28. Bartlett NL, Wilson WH, Jung SH, et al. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019; 37(21):1790-1799.
29. Thakral B, Medeiros LJ, Desai P, et al. Prognostic impact of CD5 expression in dif- fuse large B-cell lymphoma in patients treat- ed with rituximab-EPOCH. Eur J Haematol. 2017;98(4):415-421.
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