Oral Azacitidine for the Treatment of Relapsed or Refractory T-cell Large Granular Lymphocytic Leukemia

Inclusion Criteria

• Age 18 or older
• Diagnosis of T-LGLL defined as: CD3+CD8+ cell population > 650/mm^3 and the presence of a clonal T-cell receptor (within 1 month of diagnosis or relapse). This also includes patients with rare T-LGLL variants include CD4+ T-LGLL, and gamma/delta T-LGLL which can be CD4- and CD8, though patients still must have an LGL cell population > 500 cells/mm^3 and the presence of a clonal T-cell receptor within 1 month of diagnosis or relapse. Note: patients with myelodysplastic syndrome (MDS)-like T-LGLL may be included with principal investigator (PI) approval even if CD3+CD8+ cell population is < 650/mm^3, though +TCR is required. Natural-killer (NK) large granular lymphocytic leukemia (LGL) is also permitted, provided there is a clonal NK-cell population noted with > 500 cells/mm^3
• Failed at least one line of frontline therapy; off treatment for at least 14 days or 5 half-lives, whichever is longer
• Patients that have failed 3 or greater lines of therapy are eligible for the study regardless of CD3+CD8+ population or natural killer-large granular lymphocyte leukemia (NK-LGLL) population count as long as all other criteria are met
• Patients that have a known epigenetic mutation for which CC-486 is likely to have a beneficial effect (including, but not limited to EZH1, EZH2, TET2, DNMT3A), and confirmed diagnosis of T-LGLL who do not meet the T-LGLL count or NK-LGLL count may enroll on the trial with the approval of the principal investigator (PI).
• Requires 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
• Serum creatinine =< 2 x the upper limit of normal (ULN)
• 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) =< 1.5 x ULN
• Alkaline phosphatase (ALP) =< 1.5 x ULN
• Eastern cooperative oncology group (ECOG) performance status =< 2
• Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study and for 1 day after the last dosage of CC-486. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study until 1 day after the last dosage of CC-486. Male subject agrees to use an acceptable method of contraception for the duration of the study and 1 day after the last dosage of CC-486
• Able to sign informed consent

Exclusion Criteria

• Active Infection requiring ongoing anti-microbial treatment. Patients with human immunodeficiency virus (HIV), positive hepatitis B surface antigen or hepatitis C antibody will be excluded
• Concurrent immune-suppressive therapy (prednisone or equivalent up to 20 mg permitted to treat T-LGL symptoms, but must be weaned within one month of initiation of trial drug). Patients on stable, chronic prednisone =< 10 mg for rheumatologic/autoimmune conditions are exempted from this requirement. They may enroll on the study
• Active, concurrent malignancy unless deemed related to T-LGLL by PI
• Prior use of 5-azacytidine or decitabine
• Positive pregnancy test in female patients of childbearing potential
• Unstable angina or myocardial infarction within the past 2 months
• Chronic obstructive pulmonary disease or other interstitial lung disease in active exacerbation
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2 using the Modification of Diet in Renal Disease (MDRD) equation