Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia
B-cell Chronic Lymphocytic Leukemia, Leukemia, Prolymphocytic Leukemia
About this trial
This is an interventional treatment trial for B-cell Chronic Lymphocytic Leukemia
Eligibility Criteria
Inclusion Criteria:
- Histologically or cytologically confirmed diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) or prolymphocytic leukemia (PLL) arising from CLL
- No de novo PLL
- Malignant B cells must co-express CD5 with CD19 or CD20
- Patients who lack CD23 expression on their leukemia cells may not have t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma
- Must have documented lymphocytosis of > 5,000/uL
Must require therapy based on any of the following criteria:
- Massive or progressive splenomegaly and/or lymphadenopathy
- Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100,000/uL)
- Presence of weight loss > 10% over the preceding 6-month period
- NCI grade 2 or 3 fatigue
- Fevers > 100.5 F or night sweats for > 2 weeks without evidence of infection
- Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of less than 6 months
- Must have received at least one prior therapy for B-CLL
- No known brain metastases
- ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%
- Total bilirubin normal (unless due to Gilbert syndrome or compensated hemolysis)
- Life expectancy > 3 months
- Creatinine normal
- Fertile patients must use effective contraception
- Not pregnant or nursing
- Negative pregnancy test
- Any number of prior therapies allowed
- At least 1 year since prior fludarabine phosphate-rituximab combination therapy
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No chemotherapy or radiotherapy within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C)
- No other concurrent investigational agents
- AST and ALT < 2.5 times upper limit of normal
- Recovered from all prior therapy
Exclusion Criteria:
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to obatoclax mesylate or other agents used in study
- Active Coombs' positive autoimmune hemolytic anemia
- Chronic active hepatitis B patients if not on appropriate antiviral therapy (e.g., lamivudine, adefovir)
- Other neurological disorders or dysfunction or a history of seizure disorder
Uncontrolled intercurrent illness including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia including QTc > 450 msec
- Psychiatric illness/social situations that would limit compliance with study requirements
Sites / Locations
- Dana-Farber Cancer Institute
Arms of the Study
Arm 1
Experimental
Treatment (obatoclax mesylate, fludarabine, rituximab)
Patients receive obatoclax mesylate IV over 3 hours on days 1 and 3, fludarabine IV over 20-30 minutes on days 1-5, and rituximab IV over 4 hours on day 1 (days 1 and 3 of course 1 only). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo peripheral blood collection for correlative studies. Samples are analyzed for expression of pro- and anti-apoptotic Bcl-2 family members by western blot; apoptosis induction by measurement of lymphocyte count, Annexin V staining, and Caspase and PARP cleavage; activated Bax by immunoprecipitation; and Bax promoter polymorphism by PCR amplification and direct sequencing.