Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

被引：241

作者：

Tiacci, E. ^{[1
,2
,3
]}

Park, J. H. ^{[17
]}

De Carolis, L. ^{[1
,2
,3
]}

Chung, S. S. ^{[17
]}

Broccoli, A. ^{[4
]}

Scott, S. ^{[19
]}

Zaja, F. ^{[5
]}

Devlin, S. ^{[20
]}

Pulsoni, A. ^{[6
]}

Chung, Y. R. ^{[19
]}

Cimminiello, M.

Kim, E. ^{[19
]}

Rossi, D. ^{[8
]}

Stone, R. M. ^{[25
]}

Motta, G. ^{[9
]}

Saven, A. ^{[26
]}

Varettoni, M. ^{[10
]}

Altman, J. K. ^{[27
]}

Anastasia, A. ^{[11
]}

Grever, M. R. ^{[28
]}

Ambrosetti, A. ^{[12
]}

Rai, K. R. ^{[24
]}

Fraticelli, V. ^{[13
]}

Lacouture, M. E. ^{[18
]}

Carella, A. M. ^{[14
]}

Levine, R. L. ^{[17
,19
]}

Leoni, P. ^{[15
]}

Rambaldi, A. ^{[16
]}

Falzetti, F. ^{[1
,2
,3
]}

Ascani, S. ^{[1
,2
,3
]}

Capponi, M. ^{[1
,2
,3
,7
]}

Martelli, M. P. ^{[1
,2
,3
]}

Park, C. Y. ^{[19
,21
]}

Pileri, S. A. ^{[4
]}

Rosen, N. ^{[22
]}

Foa, R. ^{[6
]}

Berger, M. F. ^{[19
,23
]}

Zinzani, P. L. ^{[4
]}

Abdel-Wahab, O. ^{[17
,19
]}

Falini, B. ^{[1
,2
,3
]}

Tallman, M. S. ^{[17
]}

机构：

[1] Univ Perugia, Inst Hematol, Dept Med, I-06100 Perugia, Italy

[2] Univ Perugia, CREO, I-06100 Perugia, Italy

[3] Osped Santa Maria Misericordia, Perugia, Italy

[4] Univ Bologna, Sch Med, Units Hematol & Hematopathol, Dept Expt Diagnost & Specialty Med, Bologna, Italy

[5] Azienda Ospedaliero Univ, Dipartimento Sci Med Sperimentali & Clin, Ctr Trapianti & Terapie Cellulari Carlo Melzi, Hematol Unit, Udine, Italy

[6] Univ Roma La Sapienza, Div Hematol, Dept Cellular Biotechnol & Hematol, Rome, Italy

[7] Azienda Osped Regionale San Carlo, Hematol & Bone Marrow Transplant Unit, Potenza, Italy

[8] Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy

[9] Osped Ferrarotto, Hematol Unit, Catania, Italy

[10] Policlin San Matteo, Fdn IRCCS, Dept Onco Hematol, Pavia, Italy

[11] Spedali Civil Brescia, Hematol Unit, I-25125 Brescia, Italy

[12] Univ Verona, Sect Hematol, Dept Med, I-37100 Verona, Italy

[13] Fdn Ric & Cura SS Giovanni Paolo II, Onco Hematol Unit, Campobasso, Italy

[14] Univ San Martino, Azienda Osped, IRCCS, Ist Nazl Ric Cancro,Inst Hematol 1, Genoa, Italy

[15] Univ Osped Riuniti, Azienda Osped, Dept Hematol, Ancona, Italy

[16] Azienda Osped Papa Giovanni XXIII, Hematol & Bone Marrow Transplant Unit, Bergamo, Italy

[17] Leukemia Serv, New York, NY USA

[18] Mem Sloan Kettering Canc Ctr, Dept Med, Dermatol Serv, New York, NY 10021 USA

[19] Human Oncol & Pathogenesis Program, Dept Med, New York, NY USA

[20] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[21] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[22] Mem Sloan Kettering Canc Ctr, Dept Pharmacol, New York, NY 10021 USA

[23] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10021 USA

[24] Hofstra North Shore Long Isl Jewish Sch Med, Div Hematol Oncol, New York, NY USA

[25] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[26] Scripps Clin, Div Hematol & Oncol, La Jolla, CA 92037 USA

[27] Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[28] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2015年 / 373卷 / 18期

关键词：

MEK INHIBITION; ACTIVATION; MUTATIONS; MELANOMA; RAF; SURVIVAL; VEMURAFENIB; CLADRIBINE; PHENOTYPE; SIGNATURE;

D O I：

10.1056/NEJMoa1506583

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. METHODS We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily) - one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial. RESULTS The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism. CONCLUSIONS A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.)

引用

页码：1733 / 1747

页数：15

共 50 条

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TSCHURTSCHENTHALER, G
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[32] HAIRY-CELL LEUKEMIA
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[38] HAIRY-CELL LEUKEMIA
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[39] HAIRY-CELL LEUKEMIA
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[40] HAIRY-CELL LEUKEMIA
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