For years, immunotoxin conjugates (e.g., HA-22) have been studied in patients with relapsed disease. In patients with resistant or relapsed hairy cell leukemia expressing CD22, the immunotoxin conjugate has been reported to result in complete responses in 46% of patients [62]. Many of these patients have had durable remissions with tolerable toxicities. The recent observation that patients with classic hairy cell leukemia carry BRAF p.V600E LY294002 molecular weight within their leukemic cells prompted the exploration of the BRAF inhibitor vemurafenib in the setting of relapsed and resistant disease [63]. In patients with well-documented failures to respond to multiple standard agents, this targeted

therapy has achieved durable remissions [64], [65] and [66]. Studies in both New York and Italy are formally exploring this agent in the setting of relapsed disease. Patients have been reported to show a rapid response to vemurafenib and other BRAF V600E inhibitors. The optimal therapeutic regimen with vemurafenib has yet to

be defined. Many of the current studies simply utilize the dose and schedule derived from other trials in patients with metastatic melanoma. Considering the cutaneous toxicities, there may be other doses and schedules of administration that would provide better outcomes in hairy cell leukemia. In patients who have relapsed, a search for pathways of resistance has suggested that MEK inhibition may be equally important. Tiacci and colleagues showed that the MEK–ERK pathway has

both diagnostic and therapeutic target potentials in hairy cell leukemia [67]. In a recent brief publication, the clinical Cabozantinib cost efficacy of vemurafenib was associated with BRAF inhibition, but surprisingly there was an uncoupling with phospho-ERK as measured in the in vivo leukemic cells obtained from the patient [68]. Thus, this intriguing pathway holds promise for therapeutic intervention while presenting ample opportunity for further investigation of pharmacodynamic effects. While BRAF inhibitors provide an option for patients with classic hairy cell leukemia in need of novel therapy, patients with the variant forms of this disease require other strategies. Patients with hairy cell leukemia variant do not respond well to standard purine analog treatment with low response rates and less durable remissions. They do not have BRAF mutations, eliminating Erastin both standard therapy as well as BRAF-targeted therapies. Patients with the variant may respond to HA-22, and responses have been observed with cladribine in combination with rituximab [17]. Recently, a multi-institutional trial involving the BTK inhibitor ibrutinib has begun to enroll patients with both the classic form in relapse and the variant of this disease (http://clinicaltrials.gov/ct2/show/NCT01841723). The necessity to explore novel therapies with tolerable side effects is highly warranted, as standard therapy is associated with toxicity and limited duration of response.