Overview
This phase II trial tests whether ruxolitinib works to shrink tumors in patients with T-cell large granular lymphocyte leukemia. Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Description
PRIMARY OBJECTIVE:
I. Determine the overall response rate (ORR) of ruxolitinib in patients with T-cell large granular lymphocytic leukemia (T-LGLL) as compared to historical controls.
SECONDARY OBJECTIVES:
I. Rate of conversion from PR at 4 months to CR at 8 and 12 months (at full ruxolitinib dosage).
II. Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance) at 4, 8, 12 months.
III. Incidence of grade III/IV toxicities (at full ruxolitinib dosage). IV. Quality of life using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core 30 (C30), Health Assessment Questionnaire-Disability Index (HAQDi), Short Form (SF)-36 questionnaire at baseline, after 5 months, 1 year of treatment.
EXPLORATORY OBJECTIVE:
I. Objective benefit (OB) rate at 4 months defined as a patient that had improvement in their cytopenias, transfusion dependence but not attaining a PR.
II. Leukemia-free survival III. Progression-free survival
- OUTLINE
Patients receive ruxolitinib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity. Patients who achieve a response (CR or PR) may receive an additional 12 months of ruxolitinib, for a maximum of 24 months.
Eligibility
Inclusion Criteria:
- Age 18 or older and able to swallow pills
- Diagnosis of T-LGLL defined as: CD3+CD8+ cell population > 650/mm^3 or CD3+CD8+CD57+ population > 500/mm^3 and the presence of a clonal T-cell receptor (within 1 month of diagnosis). Note: patients with MDS-like T-LGLL may be included 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 a clonal 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 is longer
- 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 inclusion
criteria, as long as the platelet count remains >50,000/uL within 5 days of last transfusion. Note: Patients with platelets <100 x 109/L and renal impairment are not permitted to enroll to the study. Renal impairment is defined as creatinine clearance (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
of Diet in Renal Disease (MDRD) equation (multiplying eGFR by each subjects
Body Surface 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 control methods for the duration of the study. 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 treatment until 5 half-lives have passed. Male subject agrees to use an acceptable method for contraception for the duration of the study treatment until 5 half-lives have passed.
- Able to sign informed consent
Exclusion Criteria:
- Absolute neutrophil count (ANC) less than 100/mm^3
- 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 principal investigator (PI). Early stage skin cancers, prostate cancer, permitted if under no active 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 active exacerbation
- Cirrhosis