Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

Background: * Hairy cell leukemia (HCL) is an indolent B-cell leukemia comprising 2% of all leukemias, or approximately 1300 new cases per year in the US. * BRAF V600E mutation is very common in classic HCL. * HCL variant (HCLv) is wild type for BRAF and is more aggressive compared to classic HCL due to its lower response and shorter duration of response to standard purine analog chemotherapy. The median survival is only approximately 6 years compared to \>25 years for classic HCL. * CD25+ classic-appearing HCL-cells that express unmutated IGHV4-34+ immunoglobulin rearrangement, are wild-type for BRAF, and confer a poor prognosis when treated with standard purine analog chemotherapy. * While BRAF and MEK combination inhibition is making an impact in the treatment of BRAF V600E mutated HCL, this treatment is not applicable for patients with BRAF-WT HCL/HCLv. Furthermore, with poor survival outcomes in this patient population, lack of targeted therapy constitutes a clear unmet need. * Recently, several BRAF WT HCL/HCLv patients have received MEK inhibitors by compassionate use and have had lifesaving partial to complete remission, however the response has not been assessed systematically in clinical trials. * Binimetinib (also known as MEK162) is an orally bioavailable, selective and potent mitogenactivated protein (MAP) kinase (MEK1 and MEK2) inhibitor, which is approved for use in combination with encorafenib for the treatment of patients with BRAF-mutant melanoma * We have described MAP2K1 (MEK) mutations which may drive the aggressive clinical behavior of BRAF WT HCL/HCLv patients, but MEK inhibition may be clinically useful even in these patients without known MAP2K1 (MEK) mutations. Objective: -To determine the overall response rate (ORR) to binimetinib, in participants with BRAF WT HCL and HCLv. Eligibility: * BRAF WT HCL or HCLv with at least 1 prior purine analog treatment * Need for treatment as evidenced by any one of the following: ANC \<1 x10\^3/mcL, Hgb \<10g/dL, Platelet count \<100 x10\^3/mcL, leukemia cell count \>5 x10\^3/mcL, symptomatic splenomegaly, enlarging HCL mass \> 2cm in short axis. * \>= 18 years of age. * No uncontrolled infection, cardiopulmonary dysfunction, or secondary malignancy requiring treatment. * No chemotherapy, immunotherapy, investigational agent or radiotherapy within 4 weeks prior to the start of study treatment. Design: * Single arm phase 2 trial to determine ORR in participants with relapsed/refractory BRAF WT HCL and HCLv. * 2-phase minimax design will be used to rule out an unacceptable 10% in favor of an improved 25% ORR. * Initially 16 evaluable participants will be enrolled. If 2 or more achieve a major response, then accrual will continue to a total of 31 evaluable participants. * Binimetinib will be given at a dose of 45mg twice daily for as long as participants can continue dosing chronically without significant toxicity or a trial off therapy due to achievement of MRD negative complete remission or partial response (PR) / complete response (CR) in which they would like a trial off therapy. Participants may return to therapy within 2 years of stopping treatment if evidence of disease returns.