Vemurafenib in Advanced Patients with Hairy Cell Leukemia (HCL): Results of the Acsé Phase II Trial

Background:

Targeted inhibitory therapy with BRAF-inhibitors has been used successfully in HCL patients refractory to or relapsing following previous lines of therapy. The AcSé-Vemurafenib study is the second exploratory multi-tumor 2-stage design phase II trial of AcSé program. We report the preliminary results of the HCL cohort in this nationwide program.

Methods:

BRAF mutational status was assessed on INCa molecular genetic platforms by either direct sequencing or NGS. Patients with BRAF V600E mutation, progressing after at least one standard treatment and who were not amenable to curative treatment could be included in the trial and receive vemurafenib 960 mg BID for up to 16 weeks. Objective Responses (OR) were centrally assessed using clinical and biological parameters every 8 weeks. Careful selection of eligible patients is mandatory since vemurafenib might cause secondary skin malignancies, photosensitivity, QTc-prolongation, liver enzyme elevations and arthralgia. However, vemurafenib has a perfect oral bioavailability, possibility of outpatient treatment, and the lack of hematological toxicity.

A Bayesian approach allows continuous monitoring of the OR. Sequential analyses were planned after 4-month follow-up of the first 10 pts, then every 5 pts until a maximum of 30 to 50 pts, to allow early stopping using an inefficacy bound for OR of 10%. Mean OR rate was estimated with its 95% Credibility Interval (CI). If no early stopping, the treatment was be considered worthy for further evaluation if, the predictive probability that the estimated OR is higher or equal to the efficacy bound p1 =30%, is > 90%.

Results:

From 10/2014 to 04/2017, 16/32 HCL harbored BRAF V600E mutation. Ten patients were enrolled, received vemurafenib and had at least one post-baseline assessment. Median age: 68 years [46-80] and 70% men. Median number of prior chemotherapy lines: 3 (0-8). Most frequent grade ≥3 adverse events (AEs) related to vemurafenib were arthralgia (40% of patients). Among the 10 BRAF V600E HCL patients evaluable for the best overall response (BOR) with a minimum follow-up of 4 months, 6 CR and 4 PR were observed. The futility stopping rule was not reached, and the bayesian estimation of the OR rate was 91.7% [95% CI:71.5-99.8]. Median duration of response was 9.2 months [6.4-NA]. Progression-free survival (PFS) rate at 4 months was 100% and median PFS was 14.1 months [8.5-NA]. Overall 1 patient died for progression and 9 are still alive.

Conclusion:

Vemurafenib offers a feasible outpatient treatment option for relapsed/refractory patient without hematologic toxicity. These preliminary results prompt us to continue the AcSé program. Questions to be answered in the future are the optimal dosage and duration of vemurafenib, retreatment and the possibility to combine treatment with a MEK inhibitor.