Ibrutinib, an inhibitor of Bruton´s tyrosine kinase (BTK) is approved in CLL as continuous, daily administration of 420 mg orally until progression. Ibrutinib drug costs in health care are rapidly increasing and are difficult to predict, as long-term follow up analyses have shown that many patients remain on therapy for several years, in some cases even many years. It has been observed that patients who stop ibrutinib due to side effects may often remain with continued CLL disease control i.e. in stable partial remission even when off ibrutinib therapy. There are also emerging data on mutations within BTK, with loss of efficacy of ibrutinib, during long-term continuous administration. These observations raise the question whether alternative dosing strategies may be feasible. This pilot study will explore intermittent and repeated dosing of ibrutinib, until alternative therapy is required due to resistance or intolerance to ibrutinib. An "ON-OFF" dosing strategy will be applied, where advanced-phase CLL patients who have received at least 6 months of ibrutinib and who have achieved a stable PR will stop ibrutinib and be followed off therapy until clinical progression, at which ibrutinib will be re-instituted. Such "ON-OFF" ibrutinib cycles may be repeated until non-tolerability or resistance, or need of continuous dosing of ibrutinib (i.e. early progression when off the drug). If successful, the study will indicate a way forward towards reducing ibrutinib drug costs in health care without affecting long-term disease control, possibly also with fewer ibrutinib-related side effects due to a lower cumulative dose of ibrutinib. Long-term effects on potential mutations within BTK and its downstream signaling molecules will also be analysed.

Inclusion Criteria:

1. Ability to understand and voluntarily provide written informed consent and comply with the requirements of the study.

2. Age 18 years and older. There is no upper age limit in this trial.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Before start ibrutinib for the first time: diagnosed with CLL/SLL and active disease in need of treatment after having failed chemoimmunotherapy for CLL defined as a) refractory according to iwCLL criteria; or b) relapsed and deemed not suitable for additional chemo- or chemoimmunotherapy or c) del 17p and/or TP53 mutation irrespective of prior therapy.

5. Having received at least 6 months of ibrutinib therapy and having achieved at least clinical PR according to IWCLL criteria.

6. ECOG performance status of </= 2 at screening.

7. Laboratory test results:

   • Absolute neutrophil count >/= 0.5 x 109/L
   • Platelet count >/= 30 x 109/L
   • Serum creatinine < 177 µmol/L
   • ASAT (SGOT) and ALAT (SGPT) >/= 2 x ULN or >/= 5 x ULN unless attributable to CLL/SLL

8. Disease free of prior malignancies for >/= 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.

9. Agree to use reliable forms of contraception. Post-menopausal females and surgically sterilized females are exempt from this criterion.

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 or breast feeding females.
3. Any condition, including the presence of laboratory abnormalities, which according to the responsible physician places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
4. Use of any other experimental therapy within the last 14 days.
5. Concurrent use of other anti-cancer agents or treatments than ibrutinib (except a low dose of corticosteroids, max 10 mg of prednisone/day).
6. Positivity for HIV or infectious hepatitis, type A, B or C.
7. Opportunistic infections within the last 3 months.
8. Patient planned for or being a potential candidate for allo-SCT.
9. Uncontrolled hemolytic anemia or autoimmune thrombocytopenia.
10. CNS involvement or history of Richter's transformation.
11. Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon) within 28 days of the first dose of ibrutinib.
12. Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor.