提示: 手机请竖屏浏览!

利妥昔单抗治疗成人B系急性淋巴细胞白血病
Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia


Sébastien Maury ... 肿瘤 • 2016.09.15
相关阅读
• CD19 CAR治疗急性淋巴细胞白血病的长期随访研究 • tisagenlecleucel治疗儿童和年轻成人B细胞淋巴细胞白血病

摘要


背景

利妥昔单抗治疗已经改善了非霍奇金淋巴瘤患者的结局。B系急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患者也可能表达利妥昔单抗的靶点——CD20抗原。尽管单组研究提示利妥昔单抗治疗联合化疗可以改善该类患者的结局,但是这一假设尚未在随机试验中得到验证。

 

方法

我们将CD20抗原阳性、费城染色体(Philadelphia chromosome,Ph)阴性的成年ALL患者(18~59岁)随机分配为只接受化疗组或者接受利妥昔单抗治疗联合化疗组,并以无事件生存作为主要终点。在所有治疗阶段均进行了利妥昔单抗输注,共计16~18次。

 

结果

从2006年5月至2014年4月,共计入组了209名患者:105名归于利妥昔单抗组,104名归于对照组。在30个月的中位随访时间之后,利妥昔单抗组的无事件生存期比对照组长(风险比为0.66;95%置信区间[CI]为0.45~0.98;P=0.04);估计的2年无事件生存率分别为65%(95% CI为56%~75%)和52%(95% CI为43%~63%)。在多变量分析中利妥昔单抗治疗仍与更长的无事件生存期相关。两组患者间严重不良事件的总体发生率无显著性差异,但是在利妥昔单抗组中观察到对天冬酰胺酶的过敏反应更少。

 

结论

在针对ALL的化疗方案中增加使用利妥昔单抗改善了CD20抗原阳性、费城染色体阴性的ALL年轻成年患者的结局(该研究由巴黎区域临床研究办公室[Regional Clini­cal Research Office, Paris]等资助;ClinicalTrials.gov注册号为NCT00327678)。





作者信息

Sébastien Maury, M.D., Ph.D., Sylvie Chevret, M.D., Ph.D., Xavier Thomas, M.D., Ph.D., Dominik Heim, M.D., Thibaut Leguay, M.D., Françoise Huguet, M.D., Patrice Chevallier, M.D., Ph.D., Mathilde Hunault, M.D., Ph.D., Nicolas Boissel, M.D., Ph.D., Martine Escoffre‑Barbe, M.D., Urs Hess, M.D., Norbert Vey, M.D., Jean‑Michel Pignon, M.D., Thorsten Braun, M.D., Ph.D., Jean‑Pierre Marolleau, M.D., Ph.D., Jean‑Yves Cahn, M.D., Yves Chalandon, M.D., Véronique Lhéritier, R.N., M.P.H., Kheira Beldjord, Pharm.D., Ph.D., Marie C. Béné, Pharm.D., Ph.D., Norbert Ifrah, M.D., and Hervé Dombret, M.D., for GRAALL*
The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Dombret at Institut Universitaire d’Hématologie, EA-3518, Hôpital Saint-Louis, Université Paris Diderot, 1 ave. Claude Vellefaux, 75475 Paris CEDEX 10, France, or at herve.dombret@sls.aphp.fr. * A complete list of the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) centers and investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Gökbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2006; 2006: 133-41.

2. Dombret H, Cluzeau T, Huguet F, Boissel N. Pediatric-like therapy for adults with ALL. Curr Hematol Malig Rep 2014; 9: 158-64.

3. Gökbuget N, Hoelzer D. Treatment with monoclonal antibodies in acute lymphoblastic leukemia: current knowledge and future prospects. Ann Hematol 2004; 83: 201-5.

4. DeAngelo DJ. The use of novel monoclonal antibodies in the treatment of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2015; 2015: 400-5.

5. Oriol A, Ribera JM, Bergua J, et al. High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer 2008; 113: 117-25.

6. Hoelzer D, Walewski J, Döhner H, et al. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood 2014; 124: 3870-9.

7. Ribrag V, Koscielny S, Bosq J, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet 2016; 387: 2402-11.

8. Béné MC, Nebe T, Bettelheim P, et al. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10. Leukemia 2011; 25: 567-74.

9. Maury S, Huguet F, Leguay T, et al. Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. Haematologica 2010; 95: 324-8.

10. Thomas DA, O’Brien S, Jorgensen JL, et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood 2009; 113: 6330-7.

11. Thomas DA, O’Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol 2010; 28: 3880-9.

12. Hoelzer D, Gökbuget N. Chemoimmunotherapy in acute lymphoblastic leukemia. Blood Rev 2012; 26: 25-32.

13. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; 27: 911-8.

14. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007; 109: 3189-97.

15. Dhédin N, Huynh A, Maury S, et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood 2015; 125: 2486-96.

16. Beldjord K, Chevret S, Asnafi V, et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood 2014; 123: 3739-49.

17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81.

18. Cox C. Multinomial regression models based on continuation ratios. Stat Med 1988; 7: 435-41.

19. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496-509.

20. Gail M, Simon R. Testing for qualitative interactions between treatment effects and patient subsets. Biometrics 1985; 41: 361-72.

21. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13: 176-81.

22. Woo MH, Hak LJ, Storm MC, et al. Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 2000; 18: 1525-32.

23. Avramis VI, Sencer S, Periclou AP, et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 2002; 99: 1986-94.

24. Dworzak MN, Schumich A, Printz D, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood 2008; 112: 3982-8.

25. Chevallier P, Huguet F, Raffoux E, et al. Vincristine, dexamethasone and epratuzumab for older relapsed/refractory CD22+ B-acute lymphoblastic leukemia patients: a phase II study. Haematologica 2015; 100(4): e128-31.

26. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 2013; 119: 2728-36.

27. Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015; 16: 57-66.

28. Fry TJ, Mackall CL. T-cell adoptive immunotherapy for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2013; 2013: 348-53.

29. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371: 1507-17.

服务条款 | 隐私政策 | 联系我们