Vemurafenib Shows Activity in Hairy-Cell Leukemia

Hairy-cell leukemia is characterized by accumulation of malignant mature B cells and is driven by the oncogenic BRAF^V600E mutation, leading to constitutive MAPK activation. This genomic finding, together with anecdotal clinical evidence, suggests that BRAF inhibitors may be effective in hairy-cell leukemia, prompting Tiacci, Park, and colleagues to assess the efficacy and safety of short-term oral vemurafenib in hairy-cell leukemia in two multicenter phase II clinical trials. Fifty-four patients whose disease was refractory to purine analogues or who experienced relapse after purine analogue therapy received vemurafenib for a median of 16–18 weeks. In the Italian clinical trial, the overall response rate was 96% (25 of 26 evaluable patients); 35% of patients (9 of 26) achieved a complete response with a median relapse-free survival of 19 months, and 62% of patients (16 of 26) experienced a partial response with a median relapse-free survival of 6 months. In the United States study, the overall response rate in 24 patients was 100%, with 42% of patients (10 of 24) having a complete response and 58% of patients (14 of 24) achieving a partial response. The rates of progression-free survival and overall survival were 73% and 91%, respectively, with disease progression occurring in 29% of patients. The most common treatment-related adverse events in both trials were grade 1 or 2 and similar to those observed in patients with melanoma, including skin rashes, arthralgia, and secondary cutaneous tumors that were manageable by excision. Analysis of bone marrow biopsy samples revealed persistent ERK phosphorylation in residual tumor cells, and in one patient, targeted sequencing of tumor cells at relapse after vemurafenib treatment highlighted subclonal KRAS mutations, suggesting MAPK reactivation as a potential mechanism of vemurafenib resistance. These results show that short-term vemurafenib is effective in patients with relapsed or refractory hairy-cell leukemia and provide a rationale for combining vemurafenib with anti-CD20 immunotherapy or inhibitors of MEK signaling.

Tiacci E, Park JH, De Carolis L, Chung SS, Broccoli A, Scott S, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med 2015 Sep 9 [Epub ahead of print].