Background:~The standard of care for treatment of patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) has substantially changed. Current standard for patients with a relapse later than 3 years from first-line therapy is a repetition with the first-line regimen used. This poses the risk of significant immunosuppression and infectious complications as well as a shorter event-free survival as expected for first-line treatment. Current standard for patients with refractory disease, early relapse or emerging TP53 defective clones, is a targeted treatment with ibrutinib, idelalisib + rituximab or venetoclax as continuous therapy until progression or toxicity.~Rationale:~Venetoclax and ibrutinib are both oral drugs whose tolerability when used in combination is not inferior to single agents. Venetoclax and ibrutinib have complementary activity in clearing the disease across anatomical compartments. Ibrutinib is more active in lymph nodes rather than blood where a small lymphocytosis might persist despite continuous treatment. Conversely, venetoclax appears to be more active in blood and bone marrow (BM) rather than lymph nodes. By combining ibrutinib with venetoclax, cells can be mobilized from tissues into the bloodstream by ibrutinib and killed in the blood by venetoclax. Consistently, the venetoclax-ibrutinib combination can achieve undetectable minimal residual disease (MRD-neg) in a sizable proportion of patients. Gentle debulking obtained with a lead-in phase of ibrutinib monotherapy may allow starting venetoclax when the disease has been reshaped in a size that fits for low-risk of tumor lysis syndrome (TLS), a rare adverse event (AE) of venetoclax. MRD-guided treatment duration may allow patients achieving a negative status to gain drug-free intervals and less medicalization, and may avoid all the potential, and not yet completely known implications of continuous therapy on long-term safety, drug interactions, quality of life, compliance to treatment, and economic sustainability.~The primary objective of the trial is to assess efficacy after 30 cycles of trial treatment.
Venetoclax and ibrutinib have complementary activity in clearing the disease across anatomical compartments. By combining ibrutinib with venetoclax, cells can be mobilized from tissues into the bloodstream by ibrutinib and killed in the blood by venetoclax. Consistently, the venetoclax-ibrutinib combination can achieve undetectable minimal residual disease (MRD-neg) in a sizable proportion of patients. Gentle debulking obtained with a lead-in phase of ibrutinib monotherapy may allow starting venetoclax when the disease has been reshaped in a size that fits for low-risk of tumor lysis syndrome (TLS), a rare adverse event (AE) of venetoclax. MRD-guided treatment duration may allow patients achieving a negative status to gain drug-free intervals and less medicalization, and may avoid all the potential, and not yet completely known implications of continuous therapy on long-term safety, drug interactions, quality of life, compliance to treatment, and economic sustainability.