⁃ Histologically confirmed diagnosis of HCL according to morphological and immunophenotypic criteria of World Health Organization (WHO) classification \[WHO, 2008 revised 2016\] of lymphoid neoplasm. Participants should have at least one of the following indications for therapy:

∙ Absolute neutrophil count (ANC) \<1 x10(3)/mcL

‣ Hemoglobin \<10g/dL

‣ Platelets\<100 x10(3)/mcL

‣ Symptomatic splenomegaly

‣ Enlarging HCL mass \> 2cm in short axis (\>0.5cm in short axis for CNS mass)

‣ Leukemia cell count\>5x10(3)/mcL

• Participants who have eligible blood counts within 4 weeks prior to initiation of study therapy will not be considered ineligible if subsequent blood counts prior to initiation of study therapy fluctuate and become ineligible up until the time of the initiation of study therapy.

⁃ Participants must have BRAF V600 mutation as confirmed from fresh bone marrow aspirate, peripheral blood sample, or lymph node/mass by the Laboratory of Pathology, NCI. This may be done by PCR or sequence-based assays.

⁃ Participants who are ineligible for, unable to obtain in a timely manner, cannot access, unwilling to undergo or have failed Moxetumomab Pasudotox trial at NCI

⁃ Refractory or relapsed disease- defined as either:

∙ Refractory- no response or disease progression in \<=1 year following first-line treatment with a purine analog, or

‣ Relapsed- having relapsed following treatment with at least 1 prior purine-analog treatment

⁃ Age \>=18 years

⁃ Eastern Cooperative Oncology Group (ECOG) performance status \<=2 (Karnofsky \>=60%)

⁃ Participants must have adequate organ and marrow function as defined below:

∙ Total bilirubin \<= 3x upper limit of normal (ULN), unless consistent with Gilbert s (ratio between total and direct bilirubin \> 5)

‣ AST and ALT \<= 3x ULN

‣ Alkaline phosphatase \< 2.5x ULN

‣ Serum creatinine \<= 1.5 mg/dL or creatinine clearance \>= 60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal calculated using estimated glomerular filtration rate (eGFR)

‣ Serum albumin \>= 2 g/dL

‣ Prothrombin time (PT)/International Normalized Ratio (INR) \< 2.5x ULN (If on warfarin, PT/INR \< 3.5x ULN; If on any other anticoagulation, (PT) \< 2.5x ULN

‣ Fibrinogen \>= 0.5x lower limit of normal

‣ Females of childbearing potential (FOCBP) who are sexually active with a non-sterilized male partner must use a highly effective method of contraception and not donate ova prior to study entry and or the duration of study treatment and until 30 days after the last dose of study drug. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. There is a potential for encorafenib to induce CYP3A4, which may reduce the effectiveness of hormonal contraception methods. Therefore, the use of at least 1 form of non-hormonal contraception is required for females of childbearing potential during study

• treatment in this study. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are premenarchal or postmenopausal (defined as 12 months with no menses without an alternative medical cause). A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Not all methods of contraception are highly effective. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

• -Male participants must use a condom during treatment and through 90 days after the end of systemic exposure to study drug/treatment. If the male participant has a partner that is of child-bearing potential, the partner should also use contraception through

• 90 days after the end of systemic exposure to study drug/treatment. In addition, male participants must refrain from donating sperm during the study treatment and through 90 days after the end of systemic exposure to study drug/treatment. Males who have had a vasectomy qualify as having met the requirement for a highly effective birth control method.

⁃ Nursing participants must be willing to discontinue nursing from study treatment initiation through 14 days after the last dose of the study drugs.

⁃ Ability of participant to understand and the willingness to sign a written informed consent document.

⁃ Must co-enroll in study 10-C-0066: Collection of Human Samples to Study Hairy Cell and other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment