In this episode, Prof. Robin Foà and Dr. Filippo Milano sit down with Dr. Mazyar Shadman, a leading voice in immunotherapy and one of the foremost experts in chronic lymphocytic leukemia (CLL). Together, they explore how rapidly—and profoundly—the therapeutic landscape of CLL has transformed, moving away from chemo-immunotherapy toward a new era defined entirely by targeted agents.

The conversation opens with a reflection on the radical shift that has occurred in frontline management. Where fludarabine-based regimens once dominated the care of younger and fit patients, the field has now embraced treatments that no longer rely on chemotherapy at all. Randomized studies consistently show improved progression-free survival—and in some cases overall survival—making targeted therapies the undisputed standard in countries where access is guaranteed.

Against this backdrop, the speakers examine the evolving first-line strategies: continuous BTK inhibition; fixed-duration venetoclax plus obinutuzumab; and the fully oral combination of ibrutinib and venetoclax. The recent CLL17 trial, a plenary abstract at ASH, provides one of the first head-to-head comparisons among these approaches. Early results suggest that fixed-duration treatments are not inferior to continuous BTK inhibition, underscoring how meaningful “time off therapy” has become for both patients and clinicians.

A central theme of the episode is the complexity behind treatment selection. Age, comorbidities, logistical constraints, and patient preference all interplay—yet Dr. Shadman emphasizes that even in older individuals, therapeutic choices should not be dictated by age alone. For some, the simplicity of a continuous oral regimen is preferable; for others, the goal of achieving deep remission and eventually stopping therapy is paramount. Prognostic markers, particularly TP53 disruption, continue to inform expectations and guide nuanced discussions around the trade-offs between durability and freedom from treatment.

The dialogue then turns to measurable residual disease (MRD). Although MRD negativity remains an important biological milestone, Dr. Shadman cautions against extending therapy beyond predefined durations solely to chase deeper responses—except in selected high-risk settings. Ongoing studies like CLL18 may soon clarify whether MRD-guided strategies can outperform fixed-duration regimens.

One of the most challenging areas discussed is the management of double-refractory CLL. CAR-T cell therapy, while transformative in other lymphoid malignancies, has delivered only modest long-term outcomes in CLL. Early referral is critical, ideally while patients are beginning treatment with the non-covalent BTK inhibitor pirtobrutinib. Real-world data suggest that cytoreduction and disease control before CAR-T may be key to improving responses. Allogeneic transplant, though reserved for the most refractory cases, remains a necessary option for younger patients when CAR-T is not accessible or feasible.

In closing, the speakers reflect on the ultimate goal of therapy—whether cure or functional cure—and how this must be tailored to the individual sitting in front of the clinician. For some, decades of remission represent success; for others, especially the very elderly, sustained disease control may be an equally meaningful outcome. Yet global inequities remain stark: while some countries benefit from cutting-edge targeted agents, many regions still rely on chemotherapy due to economic constraints.

This episode offers a thoughtful, forward-looking examination of where CLL therapy stands today—an arena shaped by scientific progress, clinical judgment, and the persistent drive to offer patients treatments that are not only effective but also aligned with their lives and priorities.