The Braf Inhibitor Vemurafenib Plus Rituximab Produces a High Rate of Deep and Durable Responses in Relapsed/Refractory Hairy Cell Leukemia: Updated Results of a Phase‐2 Trial

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Introduction: Up to 50% of hairy cell leukemia (HCL) patients relapse after purine analogs. We identified the BRAF-V600E kinase mutation as the genetic cause of HCL (Tiacci et al., NEJM 2011). We documented, in 26 relapsed/refractory patients treated with the oral BRAF inhibitor vemurafenib for a median of 16 weeks, 96% of overall responses (including 35% complete remissions - CR), obtained after a median of 8 weeks (Tiacci et al., NEJM 2015). However, residual bone marrow (BM) HCL cells persisted even in CR cases (5-10% cells) and the median relapse-free survival in all responding patients was 9 months. Since HCL strongly expresses CD20, rituximab could improve the efficacy of BRAF inhibition by targeting leukemic cells resistant to vemurafenib. Methods: In this academic, phase-2, single-center trial (EudraCT 2014-003046-27), relapsed/refractory HCL patients received vemurafenib (960 mg b.i.d.) for 8 weeks and concomitant rituximab (375 mg/m2 i.v.) every 2 weeks. Rituximab was then given as consolidation 4 times every 2 weeks post-vemurafenib. Results: We enrolled 31 patients (median age: 59 years) with a median of 3 previous therapies. Toxicity was mostly of grade 1-2, without myelosuppression, and overlapped that of either drug when used alone. Strikingly, a CR was achieved by 26/27 (96%) evaluable cases, including 2 with delayed platelet recovery and 2 with incomplete resolution of splenomegaly who nonetheless remain in otherwise CR at 22.5 and 25 months post-treatment. The 26 CR cases, all previously treated with purine analogs, also included some patients previously refractory to rituximab (n=5) and/or who had relapsed after a prior BRAF inhibitor (n=7; 5 obtained a PR and 2 a CR after the BRAF inhibitor). Notably, a CR was obtained after just 4 weeks of vemurafenib and two doses of rituximab in 15/24 evaluable patients (63%). Measurable residual disease (MRD) by allele-specific PCR (sensitivity: 0.05% BRAF-V600E alleles) was absent in the BM of 17/26 (65%) patients; in 8/17 cases (47%), MRD clearing was obtained before rituximab consolidation. Progression-free survival (PFS) in 29 evaluable cases was 83% at a median of 29.5 months (range: 2-45) (Fig. 1A). Progressions (n=5) always occurred in MRD-positive cases, including 3/5 whose immediate prior treatment was a BRAF inhibitor (leading to PR in all 3 cases). Indeed, PFS was significantly longer in the 17 MRD-negative CR cases (100% at a median of 30.5 months) than in the 9 MRD-positive CR cases (44% at a median of 24.5 months) (p=0.001; Fig. 1B). In subsequent BM evaluations, 16/17 (94%) CR patients maintained a MRD-negative status at a median of 22.5 months (range 12.5-36.5) (Fig. 1C). Keywords: BRAF; hairy cell leukemia; minimal residual disease (MRD). Disclosures: Tiacci, E: Research Funding: Roche.