Authored by Brian Koffman, MDCM (retired), MSEd
Bottom Line:
CLL patients now have multiple excellent choices between limited-duration and continuous targeted therapies that all can offer durable disease control. Choosing between them depends on multiple factors.
Background:
The sea change in treatment for chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL / SLL) away from the more toxic and less effective chemotherapy cocktails came with the approval in February 2014 of ibrutinib, the first targeted therapy. Ibrutinib is a BTK inhibitor prescribed to be taken daily until disease progression or drug intolerance forces stopping of the medication. Continuous treatment was a new model in CLL / SLL, but one that had already revolutionized care in chronic myelogenous leukemia CML since 2001.
Many may have forgotten that when venetoclax was first approved in 2016, it was also for its use as continuous monotherapy in relapsed/refractory (R/R) CLL.
The latter BTKi approvals of acalabrutinib, followed by zanubrutinib, and most recently pirtobrutinib were all as therapies to be taken until they stopped working or could no longer be tolerated.
The same is true for less-used PI3K inhibitors, idelalisib and duvelisib.
It was not until 2018, with the approval of venetoclax plus rituximab for R/R CLL, that patients had their first fixed-duration option, followed the next year by venetoclax plus obinutuzumab for fixed-duration use frontline in CLL / SLL.
In February 2026, with the FDA approval of acalabrutinib plus venetoclax, treatment-naive CLL patients in the USA had their first approved all-oral, limited-duration therapy.
In Europe, ibrutinib and venetoclax have been approved since 2022 and are widely used globally outside the USA.
Choosing Between Continuous versus Limited Duration Therapy:
Multiple factors should go into the decision about what therapy is best for each CLL / SLL patient.
Patient Considerations:
- Patient preferences: Some patients want to be off all CLL meds so they can forget about their leukemia and avoid the expense and possible side effects, while others might prefer the reassurance of taking daily medications to knock their cancer back.
- Comorbidities: Certain conditions, such as cardiac or renal disease, can make some therapies riskier.
- Convenience: Some treatments demand frequent clinical and lab visits or even hospitalization to initiate therapy, which might be impractical and even impossible for some.
- Cost and insurance: What’s paid and what comes out of the patient’s pocket is often the decisive factor in choosing the treatment. Fixed duration might be more expensive in the short term due to the use of multiple drugs, but continuous therapies quickly become more costly long term due to the ongoing drug costs.
Research and Biologic Considerations:
- Data are sparse and early, but evidence from trials such as CLL17 demonstrated that fixed-duration therapy using venetoclax-based combinations is generally as effective as continuous BTK inhibitor therapy for first-line treatment of CLL.
- In CLL17, patients with high-risk features such as del17p do slightly better with continuous BTKi therapy, though it is not yet clear that there is a significant difference.
- More drugs usually mean more side effects.
- The addition of the anti-CD20 antibody obinutuzumab can be associated with more infections.
- Though their biologic impact can persist (especially anti-CD20 antibodies obinutuzumab and rituximab), eventually, there are no side effects from a drug you have stopped taking.
- There is emerging evidence that limiting the exposure to CLL drugs by shortening the therapy may significantly lower the risk of developing resistance mutations and allow reuse of the same drugs if the patient should have a late relapse.
The Future:
Novel fixed duration combinations with promising new drugs such as other BCL2 inhibitors (lisaftoclax and sonrotoclax) with different BTKis are in trials aimed at FDA approvals. Continuous therapies with new BTKis and a new class of drugs, BTK degraders (bexobrutideg and BGB-16673), are also in late-stage trials. Rather than an arbitrary one-size-fits-all “fixed duration” of therapy, some trials are using reaching the deep remission state of undetectable measurable residual disease (uMRD) as the signal of when to stop therapy. This method is not standard of care in the community. Finally, various drugs are being studied to “consolidate” or mop up any residual disease after a BTKi has reduced the amount of CLL, but low levels of residual disease persist. This trial is done in the hope of being able to stop all therapy.
Conclusions:
There are no bad choices. New continuous and limited-duration therapies are coming fast, and the data are growing to help inform your choice. Start by knowing what is important to you, then discuss with your healthcare team about your unique situation, and finally make a shared decision to set your best path forward.
