INCLUSION CRITERIA:
1. Men and women with histologically confirmed disease as defined by the following:
* CLL: clonal B-lymphocytosis greater than or equal to 5,000 cells/microL .
* SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic, \< 5,000 cells/microL.
* Immunophenotypic profile or immunohistochemistry read by an expert pathologist as consistent with CLL. This will include CD5, CD19, and CD20 expression by the CLL cells typically also with CD23 expression, but CD23 negative cases may be included if there is an absence of t(11;14).
2. Active disease as defined by at least one of the following (IWCLL consensus criteria):
* Weight loss greater than or equal to 10% within the previous 6 months
* Extreme fatigue
* Fevers of greater than 100.5 F for greater than or equal to 2 weeks without evidence of infection
* Night sweats for more than one month without evidence of infection
* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
* Massive or progressive splenomegaly
* Massive nodes or clusters or progressive lymphadenopathy
* Progressive lymphocytosis with an increase of \>50% over a 2-month period, or an anticipated doubling time of less than 6 months
3. Treatment naive CLL/SLL patients
-Treatment-naive CLL indicates no prior anti-CLL therapy. Anti-CLL therapy includes chemotherapies, monoclonal antibodies, and targeted agents with known or reasonably expected anti-leukemic activity.
4. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2
5. Absolute neutrophil count (ANC) \> 750/microL, platelets \> 50,000/microL
6. Agreement to use acceptable methods of contraception during the study and for 90 days after the last dose of study drug if sexually active and able to bear or beget children. Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry. Male and female subjects who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices, complete abstinence, or sterilized partner) and a barrier method (e.g. condoms, vaginal ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.
7. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)
EXCLUSION CRITERIA:
1. Transformed CLL, including Hodgkin and non-Hodgkin lymphoma
2. Active autoimmune hemolytic anemia or thrombocytopenia
3. Known bleeding disorders
4. Impaired hepatic function: Total bilirubin greater than or equal to 1.5 times upper limit of normal unless due to Gilbert's disease, aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than or equal to 2.5 times institutional upper limit of normal unless due to infiltration of liver, Child-Pugh class B or C
5. Impaired renal function: estimated glomerular filtration rate (GFR) \< 30ml/min/1.73m(2) based on CKD-EPI
6. Life-threatening illness, medical condition or organ system dysfunction which, in the investigators opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib and fludarabine, or put the study outcomes at undue risk
7. Concomitant immunomodulatory therapy, chemotherapy, radiotherapy or experimental therapy
8. Active Hepatitis B or Hepatitis C infection
9. HIV infection
10. Female patients who are currently in pregnancy, or unwilling to use acceptable methods of contraception or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol.
11. Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements.
12. Unable to understand the investigational nature of the study or give informed consent.
13. Individuals \< 18 years old
14. Known hypersensitivity to any component of ibrutinib or fludarabine
15. Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K antagonists.
16. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease-free for greater than or equal to 2 years or which will not limit survival to \< 2 years
17. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
18. History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug
19. Major surgery within 4 weeks of first dose of study drug
20. Currently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by New York Heart Association Functional Classification, or a history of myocardial infarction or unstable angina, or acute coronary syndrome within 6 months of screening.
21. Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP3A inhibitor.
