Rituximab maintenance therapy in diffuse large B-cell lympho

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10. Shen WF, Montgomery JC, Rozenfeld S, et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol. 1997;17(11):6448-6458. 11. Huang Y, Sitwala K, Bronstein J, et al. Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood. 2012;119(2):388-398. 12. Garcia-Cuellar MP, Steger J, Füller E, et al. Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia. Haematologica. 2015;100(7):905-913. 13. Aulisa L, Forraz N, McGuckin C, Hartgerink JD. Inhibition of cancer cell proliferation by designed peptide amphiphiles. Acta Biomater. 2009;5(3):842-853. 14. Carroll SB. Homeotic genes and the evolution of arthropods and chordates. Nature. 1995;376(6540):479-485. 15. Argiropoulos B, Humphries RK. Hox genes in hematopoiesis and leukemogenesis. Oncogene. 2007;26(47):6766-6776. 16. Pineault N, Helgason CD, Lawrence HJ, Humphries RK. Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol. 2002;30(1):49-57. 17. Shen WF, Krishnan K, Lawrence HJ, Largman C. The HOX homeodomain proteins block CBP histone acetyltransferase activity. Mol Cell Biol. 2001;21(21):7509-7522.

18. Ohno Y, Yasunaga S, Janmohamed S, et al. Hoxa9 transduction induces hematopoietic stem and progenitor cell activity through direct downregulation of geminin protein. PLoS One. 2013;8(1):e53161. 19. Pinsonneault J, Florence B, Vaessin H, McGinnis W. A model for extradenticle function as a switch that changes HOX proteins from repressors to activators. EMBO J.1997;16(8):2032-2042. 20. Shen WF, Rozenfeld S, Kwong A, Köm ves LG, Lawrence HJ, Largman C. HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells. Mol Cell Biol. 1999;19(4):3051-3061. 21. Schnabel CA, Jacobs Y, Cleary ML. HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis. Oncogene. 2000;19(5):608-616. 22. Moskow JJ, Bullrich F, Huebner K, Daar IO, Buchberg AM. Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol. 1995;15(10):5434-5443. 23. DiMartino JF, Selleri L, Traver D, et al. The Hox cofactor and protooncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood. 2001;98(3):618-626. 24. Dickson GJ, Liberante FG, Kettyle LM, et al. HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy. Haematologica. 2013;98(8):12161225.

Rituximab maintenance therapy in diffuse large B-cell lymphoma: is XY the most important variable?Matthew A Lunning and James O Armitage University of Nebraska Medical Center, Internal Medicine Department, Hematology/Oncology Division, Omaha, NE, USA E-mail: joarmita@unmc.edu doi:10.3324/haematol.2015.129924

n B-cell non-Hodgkin lymphomas (NHL) rituximab has extended the disease-free intervals of hundreds of tho

usands of patients. At the inception of rituximab a considerable amount of academic vigor was invested in finding the appropriate dose and frequency during induction therapy. This was followed by consideration of rituximab maintenance or extended dosing strategies. However, if maintenance rituximab does not significantly improve treatment outcomes it only represents expensive plasma. An integral step in harnessing the excitement for maintenance rituximab is to look for patients’ characteristics that can help to tailor or risk-adapt rituximab dose and/or duration of use with the goal of providing benefit to all. The primary endpoint of interest, improvement in overall survival, has only been seen in meta-analyses, leaving surrogate markers of benefit, such as event-free survival and progression-free survival in trials, to be debated at podiums and in patients’ examination rooms without a clear consensus being reached.1 The original report that triggered the spark of enthusiasm for maintenance rituximab was published by Dr. Ghielmini and colleagues and concerned patients with follicular lymphoma (FL) in whom prolonged rituximab treatment extended the duration of remission.2 The use of rituximab in FL subsequently expanded as results of randomized trials emerged showing remission prolongation with maintenance rituximab after single agent rituximab and combined rituximab-chemotherapy and then similar results in mantle cell lymphoma.3-7 A theme began to develop: rituximab maintenance was most useful in B-cell NHL subtypes in which the majority of patients do not have durable remissions. However, in diffuse large B-cell lymphoma (DLBCL), the most common NHL, in which the majority of patients who achieve a complete remissionhaematologica| 2015; 100(7)

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after rituximab-chemotherapy are cured, maintenance rituximab therapy has not been felt to be efficacious. Nevertheless, Huang and colleagues reported a randomized trial of maintenance rituximab in patients with an objective response after six cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The maintenance rituximab was administered monthly during the first 12 months and once every 3 months during the second year.8 Patients who received maintenance rituximab had a progression-free survival rate at 5 years of 45% compared to 34% in the patients who were observed (P=0.006). The overall survival rate at 5 years was 62% with maintenance rituximab and 49% with observation (P=0.03). Maintenance rituximab improved the progression-free and overall survival of patients in all International Prognostic Index groupings. The lower progression-free and overall survival rates might be expected and were probably related to the fact that all patients who had an objective response (i.e., not just complete remissions) were included in the analysis. In this study, the results were not reported by gender, so it is not possible to …… 此处隐藏：17583字，全部文档内容请下载后查看。喜欢就下载吧 ……