Ruxolitinib for the Treatment of T-Cell Large Granular Lymphocytic Leukemia

Inclusion Criteria:

• Age 18 or older and able to swallow pills

• Diagnosis of T-LGLL defined as: LGL cell population meeting diagnostic criteria (defined as CD3+CD8+ cell population >650/mm3 or CD3+CD8+CD57+ population >500/mm3or LGL cell population with other immunophenotype that includes co-expression ofCD3+, CD8+, CD57+ with >500 cells/mm3 and the presence of a clonal T-cell receptor (within 1 month of diagnosis or relapse). This also includes patients with rareT-LGLL variants include CD4+ T-LGLL, and gamma/delta T-LGLL which can be CD4- andCD8-), though patients still must have the presence of a clonal T-cell receptorwithin 1 month of diagnosis or relapse. Note: patients with MDS-like T-LGLL may beincluded with PI approval even if CD3+CD8+ cell population is < 650/mm^3, though +TCR is required. Natural-Killer (NK) LGL is also permitted, provided there is aclonal NK-cell population noted with > 500 cells/mm^3

• Untreated T-LGLL or failed at least one line of frontline therapy;

• Patients must be off treatment for at least 14 days or 5 half-lives, whichever islonger

• Require Treatment for T-LGLL (one or more required)

• Symptomatic anemia with hemoglobin < 10 g/dL

• Transfusion-dependent anemia

• Neutropenia with absolute neutrophil count (ANC) < 500/mm^3

• Neutropenia with ANC < 1500/mm^3 with recurrent infections

• Platelet count > 50 x 10^9/L. Platelet transfusion may be utilized to meet inclusioncriteria, as long as the platelet count remains >50,000/uL within 5 days of lasttransfusion. Note: Patients with platelets <100 x 109/L and renal impairment are notpermitted to enroll to the study. Renal impairment is defined as creatinineclearance (CrCl) < 90 mL/min.

• Serum creatinine =< 2 x the upper limit of normal (ULN)

• • Estimated glomerular filtration rate (eGFR) => 30 mL/min using the Modification ofDiet in Renal Disease (MDRD) equation (multiplying eGFR by each subjects BodySurface Area [BSA])

• Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome with a bilirubin > 1.5 x ULN permitted)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

• Alkaline phosphatase (ALP) =< 2.5 x ULN

• Eastern cooperative oncology group (ECOG) performance status =< 2

• Men and women of reproductive potential must agree to follow accepted birth controlmethods for the duration of the study. Female subject is either post-menopausal orsurgically sterilized or willing to use an acceptable method of birth control (i.e.,a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condomwith spermicide, or abstinence) for the duration of the study treatment until 5half-lives have passed. Male subject agrees to use an acceptable method forcontraception for the duration of the study treatment until 5 half-lives havepassed.

• Able to sign informed consent

Exclusion Criteria:

• Absolute neutrophil count (ANC) less than 100/mm^3. Note: granulocytecolony-stimulating factor (G-CSF) may be utilized to enable patients to meetinclusion criteria, as long as the ANC remains above 100/mm^3 for 5 days afteradministration of last growth-factor.

• Active infection requiring ongoing anti-microbial treatment. Patients with humanimmunodeficiency virus (HIV), positive hepatitis B surface antigen or hepatitis Cantibody will be excluded. Patients with tuberculosis risk factors will be requiredto undergo quantiferon testing and/or purified protein derivative (PPD) testing witha negative result prior to entering the study.

• Concurrent immune-suppressive therapy (prednisone or equivalent up to 20 mgpermitted to treat LGLL symptoms, but must be weaned within one month of initiationof trial drug). Patients on stable, chronic prednisone =< 10 mg forrheumatologic/autoimmune conditions are exempted from this requirement. They mayenroll on the study

• Active, concurrent malignancy unless deemed related to T-LGLL by principalinvestigator (PI). Early stage skin cancers, prostate cancer, permitted if under noactive therapy

• For females of childbearing potential: Positive pregnancy test or lactating

• Unstable angina or myocardial infarction within the past 2 months

• Chronic obstructive pulmonary disease or other interstitial lung disease in activeexacerbation

• Cirrhosis

• For any strong CYP3A4 inhibitors deemed a moderate or severe risk of interactionwith ruxolitinib, a wash-out period of 14 days, or 5 half-lives, whichever islonger, is needed prior to starting ruxolitinib

• Given the CYP3A4 inhibition potential of grapefruit, grapefruit juice, Sevilleorange juice, pomelos, and starfruits, patients will need to refrain from thesefoods/drinks for 14 days prior to initiation of therapy, and throughout the studyperiod