A Study of Ruxolitinib and Duvelisib in People With Lymphoma

Inclusion Criteria: a) Pathologically-confirmed mature T-cell lymphomas at the enrolling institution. Permitted histologies include (for dose escalation and expansion): i) Stage ≥Ib CTCL, which has relapsed or progressed after at least two systemic therapies. In order to ensure balanced enrollment for patients with systemic T-cell lymphoma and CTCL, a maximum of 15 CTCL patients will be enrolled in expansion cohort. ii) Systemic anaplastic large cell lymphoma that has relapsed after therapy containing brentuximab vedotin. iii) T-cell prolymphocytic leukemia (treatment naïve permitted) For the following histologies, patients are required to have received at least 1 prior therapy (dose escalation and expansion): iv) T-cell large granular lymphocytic leukemia v) Aggressive NK-cell leukemia vi) Adult T-cell leukemia/lymphoma vii) Extranodal NK/T- cell lymphoma, nasal type viii) Enteropathy-associated T-cell lymphoma ix) Monomorphic epitheliotropic intestinal t-cell lymphoma x) Hepatosplenic T cell lymphoma xi) Subcutaneous panniculitis-like T-cell lymphoma xii) Primary cutaneous anaplastic large cell lymphoma xiii) Primary cutaneous gamma/delta T-cell lymphoma xiv) Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma xv) Peripheral T-cell lymphoma, not otherwise specified xvi) Angioimmunoblastic T cell lymphoma xvii) Follicular T-cell lymphoma xviii) Nodal peripheral T-cell lymphoma wih T follicular helper phenotype b) Nodal periphal T-cell lymphoma wih T follicular helper phenotype Specific for T-PLL and TFH lymphoma expansion: histologies must be pathologically confirmed at the enrolling institutions i) T-cell prolymphocytic leukemia (treatment naïve permitted) ii) T-follicular helper lymphomas (must have received at least 1 prior treatment) c) Age ≥18 years at time of enrollment d) Performance status, as assessed in the ECOG grading system, ≤2 e) Laboratory criteria. Laboratory criteria i) For dose escalation phase: 1. Absolute neutrophil count ≥1.0 K/mcL (Note: growth factor is allowed) 2. Platelet count ≥80 K/μl or ≥50 K/μl if due to lymphoma 3. Creatinine ≤1.5 × ULN OR Measured calculated creatinine clearance ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN i. Creatinine clearance should be calculated per institutional standard d. Direct bilirubin ≤1.5x upper limit of normal (ULN) or ≤3x ULN if documented hepatic involvement with lymphoma, or ≤5x ULN if history of Gilbert's syndrome; AST and ALT ≤ 3x ULN; or ≤ 5x ULN if due to lymphoma involvement ii) For dose expansion phase and T-PLL/TFH lymphoma expansion: 1. Absolute neutrophil count ≥1.0 K/mcL or ≥0.5 K/mcL if due to lymphoma or ≥0.0 K/mcL if due to T-PLL or large granular lymphocytic leukemia (LGL) (Note: growth factor is allowed). 2. Platelet count ≥80 K/μl or ≥50 K/μl if due to lymphoma 3. c. Creatinine ≤1.5 × ULN OR Measured calculated creatinine clearance ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN i. Creatinine clearance should be calculated per institutional standard d. Direct bilirubin ≤1.5x upper limit of normal (ULN) or ≤3x ULN if documented hepatic involvement with lymphoma, or ≤5x ULN if history of Gilbert's syndrome; AST and ALT ≤ 3x ULN; or ≤ 5x ULN if due to lymphoma involvement f) Measurable disease, defined by at least one of the following: * Revised International Working Group Classification for systemic lymphoma19 * Atypical T lymphocytes quantifiable by flow cytometry or morphology in the peripheral blood or bone marrow * mSWAT (Modified Severity Weighted Assessment Tool) \>0 g) Ability to swallow pills h) Women of reproductive potential\* must have a negative serum or urine β human chorionic gonadotropin (βhCG) pregnancy test within 14 days of initiating therapy. All women of reproductive potential and all sexually active male patients must agree to use adequate methods of birth control (e.g. latex condoms) throughout the study and for 3 months after the last dose of study drug. * A woman of reproductive potential is a sexually-mature woman who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months). * The effects of duvelisib on conception, pregnancy, and lactation are unknown. Since duvelisib has not been evaluated in pregnant or nursing women, the treatment of pregnant women or women of childbearing potential who are not using a highly effective contraception is contraindicated. Exclusion Criteria: 1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. 2. Pregnant women. (Lactating women must agree not to breast feed while taking study medications). 3. Prior allogeneic stem cell transplant within 6 months of starting treatment or patients with active GVHD requiring immunosuppression. a. Prior allogeneic stem cell transplant may be allowed after discussion with MSK PI if no GVHD or immunosuppression is present at time of enrollment... d) Prior use of duvelisib or ruxolitinib if either agent was discontinued due to toxicity. e) Previous systemic anti-cancer therapy for TCL within 14 days of initiating study drug a. Patients who have received localized RT as part of their immediate prior therapy may be allowed to enroll with shorter washout period after discussion with the MSK Principal Investigator. i. Patients receiving treatment with single agent ruxolitinib or duvelisib may be allowed to enroll onto the study without a washout period b. Systemic corticosteroids must be tapered to 20mg/day or less prednisone (or equivalent) upon start of investigational treatment. c. Topical steroids for CTCL is permitted on study. f) Ongoing use of immunosuppressant medications, including corticosteroids greater than 20mg of prednisone o