Leukemia | 2021
Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial
Abstract
Hairy-cell leukemia (HCL) is a rare indolent B-cell neoplasm that responds very well to chemotherapy with purine analogs (cladribine and pentostatin), but relapses are frequent (up to 58% in younger patients) [1, 2] and progressively less sensitive to these myelotoxic and immunesuppressive drugs. Our discovery that the BRAF-V600E mutation is the genetic lesion underlying HCL [3–5] and shaping the morphologic, molecular and anti-apoptotic features of leukemic cells [6], opened the way to BRAF inhibition as targeted therapeutic strategy in this disease [7, 8]. Thus, we and others assessed the safety and efficacy of a short course of vemurafenib (an oral BRAF inhibitor clinically effective in BRAF-V600E+melanoma [9]) delivered to 50 evaluable relapsed/refractory HCL patients enrolled in two phase-2 clinical trials [10]. Vemurafenib (given for a median of 16 or 18 weeks) produced 96–100% overall responses (ORs) and 35–42% complete responses (CRs), all with measurable residual disease (MRD) [10]. In our trial with longer follow-up, the median survival free from relapse of cytopenias in the 25 patients reaching an OR was 9 months after the end of treatment [10]. Our pre-clinical studies on patients’ HCL cells showed a promising anti-leukemic activity also for dabrafenib [6], another oral reversible ATP-competitive BRAF inhibitor approved in BRAF-V600E+metastatic melanoma [11]. Dabrafenib anti-leukemic activity was anecdotally reported also in single HCL patients, but response was not thoroughly documented [12] or disease burden was relatively limited [13] and did not clearly meet standard criteria for initiating treatment in HCL [14]. Therefore, we conducted a pilot phase-2 academic single-center clinical trial (EudraCT-2014001379-29) to prospectively assess dabrafenib safety and efficacy in 10 relapsed/refractory BRAF-V600E+HCL patients, including 2 who had been treated with vemurafenib within our previous trial [10]. Enrollment of the 10 patients (completed in 9 months) followed a Simon minimax statistical design aiming at an OR rate ≥60% (versus <20% as null hypothesis) with α= 0.05 and β= 0.2. Key inclusion criteria (see also Supplementary Appendix) were: (i) disease refractory to, or relapsing ≤2 years after, the first course of purine analog, or relapsing whenever after a second or later course, or unsuitable to chemotherapy for patient comorbidites and/or old age; and (ii) disease requiring treatment for cytopenia(s) (neutrophils <1500/mm, platelets <100,000/mm and/or hemoglobin <11 g/dl). Dabrafenib was given orally at its standard dose of 150mg twice daily for 8 weeks, followed by additional 4 weeks if no CR was obtained after 8 weeks. Response assessment, including splenic ultrasound and bone marrow (BM) evaluation, was performed every 4 weeks of dabrafenib dosing. Blood counts and chemistry were obtained weekly during the first 4 weeks, every 2 weeks thereafter during treatment, and every 3 months during follow-up. To monitor for dabrafenib toxicities, patients also underwent dermatologic examinations every 4 weeks and electrocardiograms every 2 weeks during treatment. * Enrico Tiacci [email protected]