Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia Journal Article


Authors: Tiacci, E.; Park, J. H.; De Carolis, L.; Chung, S. S.; Broccoli, A.; Scott, S.; Zaja, F.; Devlin, S.; Pulsoni, A.; Chung, Y. R.; Cimminiello, M.; Kim, E.; Rossi, D.; Stone, R. M.; Motta, G.; Saven, A.; Varettoni, M.; Altman, J. K.; Anastasia, A.; Grever, M. R.; Ambrosetti, A.; Rai, K. R.; Fraticelli, V.; Lacouture, M. E.; Carella, A. M.; Levine, R. L.; Leoni, P.; Rambaldi, A.; Falzetti, F.; Ascani, S.; Capponi, M.; Martelli, M. P.; Park, C. Y.; Pileri, S. A.; Rosen, N.; Foà, R.; Berger, M. F.; Zinzani, P. L.; Abdel-Wahab, O.; Falini, B.; Tallman, M. S.
Article Title: Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia
Abstract: 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 hairycell 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. © 2015 Massachusetts Medical Society.
Keywords: mitogen activated protein kinase; adult; clinical article; human tissue; protein phosphorylation; treatment response; aged; aged, 80 and over; disease-free survival; middle aged; survival rate; oncoprotein; gene mutation; human cell; overall survival; genetics; mutation; proto-oncogene proteins; clinical trial; cancer recurrence; squamous cell carcinoma; drug dose reduction; drug safety; side effect; treatment duration; antineoplastic agents; united states; drug targeting; disease free survival; follow up; antineoplastic agent; biological marker; biological markers; melanoma; progression free survival; phase 2 clinical trial; bone marrow; basal cell carcinoma; nausea; recurrence; creatinine; creatinine blood level; drug resistance; pathology; drug resistance, neoplasm; hyperkeratosis; abdominal pain; aminotransferase blood level; arthralgia; asthenia; fever; rash; alkaline phosphatase; bilirubin; blood; bone marrow biopsy; sulfonamide; multicenter study; sulfonamides; arthritis; pancreatitis; panniculitis; erythema; remission; remission induction; seborrheic keratosis; recurrent disease; ras protein; alkaline phosphatase blood level; hyperbilirubinemia; headache; skin papilloma; ras proteins; aminotransferase; indoles; leukemia relapse; triacylglycerol lipase blood level; administration, oral; alopecia; indole derivative; bilirubin blood level; b raf kinase; photosensitivity; treatment withdrawal; proto-oncogene proteins b-raf; braf protein, human; kras protein, human; fibrinogen; fibrinogen blood level; interleukin 2 receptor alpha; triacylglycerol lipase; exanthema; oral drug administration; braf gene; hairy cell leukemia; recurrence free survival; dysesthesia; italy; musculoskeletal pain; palmoplantar keratoderma; vemurafenib; foot pain; leukemia, hairy cell; very elderly; interleukin 1 receptor type ii; hand pain; humans; human; male; female; priority journal; article; antagonists and inhibitors; chemically induced; refractory hairy cell leukemia; relapsed hairy cell leukemia
Journal Title: New England Journal of Medicine
Volume: 373
Issue: 18
ISSN: 0028-4793
Publisher: Massachusetts Medical Society  
Date Published: 2015-10-29
Start Page: 1733
End Page: 1747
Language: English
DOI: 10.1056/NEJMoa1506583
PUBMED: 26352686
PROVIDER: scopus
PMCID: PMC4811324
DOI/URL:
Notes: Export Date: 2 December 2015 -- Source: Scopus
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MSK Authors
  1. Mario E Lacouture
    276 Lacouture
  2. Neal Rosen
    366 Rosen
  3. Martin Stuart Tallman
    443 Tallman
  4. Jae Hong Park
    147 Park
  5. Stephen Shiu-Wah Chung
    58 Chung
  6. Ross Levine
    490 Levine
  7. Michael Forman Berger
    392 Berger
  8. Christopher Yongchul Park
    89 Park
  9. Sean McCarthy Devlin
    305 Devlin
  10. Young Rock Chung
    46 Chung
  11. Sasinya Neka Scott
    66 Scott
  12. Eunhee Kim
    28 Kim