Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia

• Published in: Blood 2023-03, Vol.141 (9), p.996-1006
• Main Authors: Kreitman, Robert J., Moreau, Philippe, Ravandi, Farhad, Hutchings, Martin, Gazzah, Anas, Michallet, Anne-Sophie, Wainberg, Zev A., Stein, Alexander, Dietrich, Sascha, de Jonge, Maja J. A., Willenbacher, Wolfgang, De Grève, Jacques, Arons, Evgeny, Ilankumaran, Palanichamy, Burgess, Paul, Gasal, Eduard, Subbiah, Vivek
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Clinical Trials and Observations; Humans; Leukemia, Hairy Cell - drug therapy; Leukemia, Hairy Cell - genetics; Mutation; Oximes - adverse effects; Proto-Oncogene Proteins B-raf - genetics; Pyridones - adverse effects; Pyrimidinones - adverse effects
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021013658

•Dabrafenib + trametinib showed durable responses with a manageable safety profile in patients with relapsed/refractory BRAF V600E–mutant HCL.•This combination should be considered a meaningful therapeutic option for patients with relapsed/refractory BRAF V600E–mutant HCL. [Display omitted] BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110. BRAF V600E mutation is present in 90% of hairy cell leukemia (HCL). Targeted therapy with BRAF inhibitors is effective in relapsed/refractory HCL, but relapses are frequent. Kreitman and colleagues report that combined therapy with the BRAF inhibitor dabrafenib and trametinib, which targets downstream MEK, is highly effective, resulting in 89%