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维莫非尼联合利妥昔单抗治疗难治性或复发性毛细胞白血病
Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia


Enrico Tiacci ... 肿瘤 • 2021.05.13
相关阅读
• 靶向毛细胞白血病

摘要


背景

毛细胞白血病(HCL)是CD20+惰性B细胞癌,其中BRAF V600E激酶激活突变起着致病作用。在纳入难治性或复发性HCL患者的临床试验中,应用口服BRAF抑制剂维莫非尼靶向BRAF V600E可使91%的患者达到缓解,使35%的患者达到完全缓解。然而,停药后的中位无复发生存期只有9个月。


方法

在纳入难治性或复发性HCL患者的2期、单中心、学术性试验中,我们评估了维莫非尼(每日2次,每次960 mg,给药8周)联合同期和序贯利妥昔单抗(375 mg/m2体表面积,在18周期间给药8次)治疗的安全性和疗效。主要终点是在计划的治疗结束时达到完全缓解。


结果

在本试验纳入的30例HCL患者中,既往接受过的治疗种数中位数为3种。在意向治疗人群中,本试验观察到26例患者(87%)达到完全缓解。所有化疗(10例)或利妥昔单抗(5例)难治性HCL患者,以及所有接受过BRAF抑制剂治疗(7例)的患者,均达到完全缓解。血小板减少症在中位2周后消退,中性粒细胞减少症在中位4周后消退。在26例完全缓解的患者中,17例(65%)清除了微小残留病变(MRD)。在中位37个月随访时,全部30例患者的无进展生存率为78%;在中位34个月随访时,26例达到缓解患者的无复发生存率为85%。在事后分析中,MRD阴性和既往未接受过BRAF抑制剂治疗与较长的无复发生存期相关。毒性作用(大多为1级或2级)均为既往已在这些药物中观察到的毒性作用。


结论

在此项小规模研究中,维莫非尼联合利妥昔单抗这一不含化疗药物且无骨髓毒性的短疗程治疗方案,使大多数难治性或复发性HCL患者达到持久完全缓解(由欧洲研究理事会[European Research Council]等资助,HCL-PG03在EudraCT注册号为2014-003046-27)。





作者信息

Enrico Tiacci, M.D., Luca De Carolis, M.D., Edoardo Simonetti, M.D., Monia Capponi, M.D., Achille Ambrosetti, M.D., Eugenio Lucia, M.D., Agostino Antolino, M.D., Alessandro Pulsoni, M.D., Samantha Ferrari, M.D., Pier L. Zinzani, M.D., Stefano Ascani, M.D., Vincenzo M. Perriello, M.D., Luigi Rigacci, M.D., Gianluca Gaidano, M.D., Roberta Della Seta, M.D., Natalia Frattarelli, M.D., Paolo Falcucci, M.D., Robin Foà, M.D., Giuseppe Visani, M.D., Francesco Zaja, M.D., and Brunangelo Falini, M.D.
From the Institute of Hematology, Ospedale S. Maria della Misericordia, and the Department of Medicine, University of Perugia, Perugia (E.T., L.D.C., E.S., M.C., S.A., V.M.P., B.F.), the Department of Medicine, Section of Hematology, University of Verona, Verona (A. Ambrosetti), the Hematology Unit, Ospedale di Cosenza, Cosenza (E.L.), the Hematology Unit, Department of Transfusional Medicine–SIMMT, Maria Paternò-Arezzo Hospital, Ragusa (A. Antolino), the Hematology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome (A.P., R.F.), and the Hematology and Stem Cell Transplant Unit, A.O. San Camillo Forlanini (L.R.), Rome, the Department of Hematology, Spedali Civili di Brescia, Brescia (S.F.), IRCCS Azienda Ospedaliero–Universitaria di Bologna, Istituto di Ematologia “Seràgnoli” and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna (P.L.Z.), the Department of Translational Medicine, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara (G.G.), the Hematology Unit, Ospedale di Carrara, Carrara (R.D.S.), the Hematology Unit, Ospedale di Frosinone, Frosinone (N.F.), the Hematology Unit, Ospedale di Ronciglione, Viterbo (P.F.), the Hematology Unit, Ospedale di Pesaro, Pesaro (G.V.), and the Hematology Unit, Azienda Sanitaria Universitaria Integrata–Ospedale Maggiore, Trieste (F.Z.) — all in Italy. Address reprint requests to Dr. Tiacci or Dr. Falini at Centro di Ricerche Emato-Oncologiche, Ospedale S. Maria della Misericordia, Blocco R, Piano 2, Piazzale Menghini 8, 06132 Perugia, or at enrico.tiacci@unipg.it and brunangelo.falini@unipg.it, respectively.

 

参考文献

1. Foucar K, Falini B, Stein H. Hairy cell leukaemia. In: Swerdlow S, Campo E, Harris NL, et al., eds. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon, France: International Agency for Research on Cancer, 2017:226-228.

2. Tiacci E, Liso A, Piris M, Falini B. Evolving concepts in the pathogenesis of hairy-cell leukaemia. Nat Rev Cancer 2006;6:437-448.

3. Falini B, Martelli MP, Tiacci E. BRAF V600E mutation in hairy cell leukemia: from bench to bedside. Blood 2016;128:1918-1927.

4. Grever MR. How I treat hairy cell leukemia. Blood 2010;115:21-28.

5. Maitre E, Cornet E, Troussard X. Hairy cell leukemia: 2020 update on diagnosis, risk stratification, and treatment. Am J Hematol 2019;94:1413-1422.

6. Benz R, Arn K, Andres M, et al. Prospective long-term follow-up after first-line subcutaneous cladribine in hairy cell leukemia: a SAKK trial. Blood Adv 2020;4:3699-3707.

7. Paillassa J, Cornet E, Noel S, et al. Analysis of a cohort of 279 patients with hairy-cell leukemia (HCL): 10 years of follow-up. Blood Cancer J 2020;10:62-62.

8. Rosenberg JD, Burian C, Waalen J, Saven A. Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single-institution series. Blood 2014;123:177-183.

9. Else M, Dearden CE, Catovsky D. Long-term follow-up after purine analogue therapy in hairy cell leukaemia. Best Pract Res Clin Haematol 2015;28:217-229.

10. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011;364:2305-2315.

11. Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 2012;119:192-195.

12. Tiacci E, Pettirossi V, Schiavoni G, Falini B. Genomics of hairy cell leukemia. J Clin Oncol 2017;35:1002-1010.

13. Tiacci E, Schiavoni G, Martelli MP, et al. Constant activation of the RAF-MEK-ERK pathway as a diagnostic and therapeutic target in hairy cell leukemia. Haematologica 2013;98:635-639.

14. Pettirossi V, Santi A, Imperi E, et al. BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood 2015;125:1207-1216.

15. Falini B, Tiacci E. New treatment options in hairy cell leukemia with focus on BRAF inhibitors. Hematol Oncol 2019;37:Suppl 1:30-37.

16. Chakraborty R, Abdel-Wahab O, Durham BH. MAP-kinase-driven hematopoietic neoplasms: a decade of progress in the molecular age. Cold Spring Harb Perspect Med 2020 June 29 (Epub ahead of print).

17. Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T. BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med 2012;366:2038-2040.

18. Vergote V, Dierickx D, Janssens A, et al. Rapid and complete hematological response of refractory hairy cell leukemia to the BRAF inhibitor dabrafenib. Ann Hematol 2014;93:2087-2089.

19. Dietrich S, Pircher A, Endris V, et al. BRAF inhibition in hairy cell leukemia with low-dose vemurafenib. Blood 2016;127:2847-2855.

20. Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med 2015;373:1733-1747.

21. Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood 2003;102:810-813.

22. Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood 2017;129:553-560.

23. Tiacci E, De Carolis L, Simonetti E, et al. Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial. Leukemia 2021 March 17 (Epub ahead of print).

24. Sarid N, Ahmad HN, Wotherspoon A, Dearden CE, Else M, Catovsky D. An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy. Br J Haematol 2015;171:784-787.

25. Raspadori D, Rondelli D, Birtolo S, et al. Long-lasting decrease of CD4+/CD45RA+ T cells in HCL patients after 2-chlorodeoxyadenosine (2-CdA) treatment. Leukemia 1999;13:1254-1257.

26. Kreitman RJ, Dearden C, Zinzani PL, et al. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia 2018;32:1768-1777.

27. Sigal DS, Sharpe R, Burian C, Saven A. Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine. Blood 2010;115:1893-1896.

28. Ortiz-Maldonado V, Villamor N, Baumann T, et al. Is there a role for minimal residual disease monitoring in the management of patients with hairy-cell leukaemia? Br J Haematol 2018;183:127-129.

29. Brown NA, Betz BL, Weigelin HC, Elenitoba-Johnson KSJ, Lim MS, Bailey NG. Evaluation of allele-specific PCR and immunohistochemistry for the detection of BRAF V600E mutations in hairy cell leukemia. Am J Clin Pathol 2015;143:89-99.

30. Gupta GK, Sun X, Yuan CM, Stetler-Stevenson M, Kreitman RJ, Maric I. Usefulness of dual immunohistochemistry staining in detection of hairy cell leukemia in bone marrow. Am J Clin Pathol 2020;153:322-327.

31. Kreitman RJ, Tallman MS, Robak T, et al. Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up. Blood 2018;131:2331-2334.

32. Shenoi DP, Andritsos LA, Blachly JS, et al. Classic hairy cell leukemia complicated by pancytopenia and severe infection: a report of 3 cases treated with vemurafenib. Blood Adv 2019;3:116-118.

33. Bohn J-P, Pircher A, Wanner D, et al. Low-dose vemurafenib in hairy cell leukemia patients with active infection. Am J Hematol 2019;94(6):E180-E182.

34. Lee LYW, Cazier J-B, Starkey T, et al. COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study. Lancet Oncol 2020;21:1309-1316.

35. Glenthøj A, Jakobsen LH, Sengeløv H, et al. SARS-CoV-2 infection among patients with haematological disorders: severity and one-month outcome in 66 Danish patients in a nationwide cohort study. Eur J Haematol 2021;106:72-81.

36. Grever MR, Andritsos L, Banerji V, et al. Hairy cell leukemia and Covid-19: adaptation of treatment guidelines. Leukemia (in press).

37. Chihara D, Kantarjian H, O’Brien S, et al. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol 2016;174:760-766.

38. Chihara D, Arons E, Stetler-Stevenson M, et al. Randomized phase II study of first-line cladribine with concurrent or delayed rituximab in patients with hairy cell leukemia. J Clin Oncol 2020;38:1527-1538.

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