Although contemporary guidelines provide recommendations on therapeutic sequencing for patients with chronic lymphocytic leukemia (CLL), there is no established optimal treatment sequence. CLL treatment is therefore individualized based on patient and disease characteristics.

We now have many effective treatment options for managing CLL. When choosing treatment in the frontline setting, one important attribute that I consider is whether the CLL cells carry del(17p) or a TP53 mutation. Several studies have shown that patients with these aberrations benefit from continuous BTK inhibitor–based treatment. At the 65th American Society of Hematology Annual Meeting and Exposition in 2023, Wiestner and colleagues presented updated data from a phase 2 study of patients with del(17p)/TP53 mutation who received continuous ibrutinib. The median progression-free survival was 81 months, and the median overall survival was not reached. Benefits in progression-free survival for these patients have also been shown with acalabrutinib and zanubrutinib, although the follow-up from these agents in patients with del(17p)/TP53 mutation is shorter compared with ibrutinib.

In the absence of TP53 disruption, we generally choose between 2 major treatment types: continuous BTK inhibitor–based treatment or fixed-duration therapy with venetoclax and obinutuzumab. There are no head-to-head comparison trials to help guide which treatment strategy is better. Therefore, the treatment choices rely on patients’ comorbidities, their treatment preferences, and the expected side-effect profile of each drug. For example, patients who might have difficulty with adhering to the 5-week ramp-up dosing schedule for venetoclax and with coming into the office for obinutuzumab infusions would be preferentially treated with continuous BTK inhibitor–based treatments. On the other hand, if a patient is thinking about fixed-duration therapy or if the patient’s comorbidities lead us to predict an increased risk of adverse consequences from BTK inhibitor–based treatment (including an increased risk of hypertension, atrial fibrillation, or bleeding), I think that they are ideally suited for venetoclax and obinutuzumab. A careful discussion of all the pros and cons of each treatment approach is generally required prior to proceeding with treatment.

I would like to emphasize that the optimal treatment sequencing remains unclear. Thankfully, data suggest that salvage therapy with the other treatment category can work regardless of the treatment chosen in the frontline setting. Frontline clinical trials are in progress, in particular the phase 3 CLL17 trial, which enrolled patients and randomized them 1:1:1 to continuous ibrutinib, fixed-duration therapy with venetoclax and obinutuzumab, or fixed-duration therapy with venetoclax and ibrutinib. The results will hopefully inform the upfront treatment approach in CLL. Until then, I recommend a pragmatic approach, taking into account the patient’s clinical characteristics, comorbidities, and expected toxicities, except among those with del(17p)/TP53 mutation, for whom I recommend continuous BTK inhibitor–based treatment (generally a second-generation covalent BTK inhibitor).

Finally, challenges remain in treating patients whose disease progresses after both classes of agents have been used, which is known as double-refractory CLL. We have some US Food and Drug Administration (FDA)–approved treatment options in this case, including PI3K inhibitors and, more recently, the noncovalent BTK inhibitor pirtobrutinib and the CAR T-cell therapy lisocabtagene maraleucel. Given their toxicity profile, PI3K inhibitors have a very limited role in the treatment of patients with relapsed CLL; hence, I typically do not use them in my practice. There are also many ongoing clinical trials that show promise in treating double-refractory CLL, including those that use bispecific antibodies, BTK degraders, and other noncovalent BTK inhibitors.