In chronic lymphocytic leukemia (CLL), targeted drugs are superior to chemo-immunotherapy (CIT) in terms of efficacy and tolerability across most patient subgroups and, hence, are currently recommended as standard treatment of choice in various international treatment guidelines [1]. In particular, CLL patients with high-risk genetic alterations such as unmutated immunoglobulin heavy-chain variant region (IGHV) status, TP53 aberrations, and/or a complex karyotype derive major benefits with these novel agents compared to CIT. However, acquired resistance and drug intolerability typically associated with continuous treatment remain major challenges to overcome in daily clinical practice, thereby predisposing patients to multiple lines of therapy in the course of the disease [2]. Fixed-duration, mostly chemotherapy-free, treatment approaches are being investigated to induce deep remissions negative for minimal residual disease (MRD), reduce clonal evolution, and improve drug tolerability in several prospective clinical trials [3]. In the absence of available data from the prospective randomized clinical trial CLL17, notably CLL patients carrying a TP53 alteration may succumb to inferior PFS outcomes with currently licensed fixed-duration regimens. Hence, most current CLL guidelines, such as Onkopedia, favor the use of continuous treatment with inhibitors of BTK (BTKi) in this patient subpopulation [4]. At ICML 2023, the long-term outcomes of the CLL14 registration trial for 1‑year venetoclax-obinutuzumab (Ven-Obi) in untreated CLL patients were updated. With a median follow-up of 76.4 months, the significant benefit in PFS for Ven-Obi versus chlorambucil-obinutuzumab was maintained across all risk groups. Notably, Ven-Obi achieved a median PFS of 52 months in patients with a TP53 dysfunction and a median PFS of 65 months in those with an unmutated IGHV status (UM-IGHV). Yet, the adverse prognostic effect associated with these high-risk genetic abnormalities still remains to be fully compensated as they constitute independent negative prognostic factors with Ven-Obi, as identified by multivariate analysis. In addition, Kaplan–Maier curves for MRD negativity have still not reached a plateau, indicating further disease recurrences with longer follow-up. Nevertheless, over 50% of patients currently remain in remission 5 years after the end of treatment and nearly two thirds of patients have yet not required second-line therapy [5].

Even longer follow-up is needed to help elucidate whether Ven-Obi indeed achieves long-term remissions reminding us of cure as did fludarabine-cyclophosphamide-rituximab (FCR) in the subgroup of fit patients with mutated IGHV (M-IGHV; [6]). At ICML 2023, long-term data were presented from the phase 2 trial NCT02251548 investigating whether FCR in combination with ibrutinib followed by ibrutinib maintenance for at least 2 years induces deep and durable remissions irrespective of the IGHV mutation status in 85 untreated fit CLL patients, including 53% with UM-IGHV and 6% with dysfunctional TP53. With a median follow-up of 63 months, 5‑year PFS was 94% and 5‑year overall survival (OS) was 99%. Survival outcomes were similar for patients with (U)M-IGHV and irrespective of the duration of ibrutinib maintenance treatment. Overall, 77% of patients were negative for MRD after 2‑year ibrutinib maintenance. Of interest, thereafter patients were not only tracked for MRD recurrence in the peripheral blood (PB, detected in 13 patients, 62% with U‑IGHV), but also for novel acquired driver mutations at this time point. Of these patients, 23% presented with novel TP53 mutations, 38% with mutations in NOTCH1, SF3B1, ATM, XPO1, and/or BRAF. Of note, re-emerging clones lacked BTKi resistance mutations retaining sensitivity to ibrutinib. As such, ibrutinib retreatment achieved partial remission (PR) in 67% of cases (4/6 patients), but did not facilitate second eradication of MRD with a median duration of treatment of 34 months. Study treatment was generally well tolerated with atrial fibrillation in 8% of patients, second malignancies in 11% of patients, mostly non-melanoma skin cancers, and one sudden cardiac death during ibrutinib maintenance [7]. In view of high MRD negativity, sustained sensitivity to ibrutinib at relapse and no significant additional toxicity, these early clinical data favor further investigation of FCR plus ibrutinib in randomized studies.

Another strategy to facilitate long-term MRD-negative remissions and reduce toxicity encompasses fixed-duration triple treatment with BTKi, BCL2i and obinutuzumab. At ICML 2023, an update of the phase 2 BOVEN trial was given. The trial investigates the combination of venetoclax, the second-generation covalent BTKi zanubrutinib and obinutuzumab in 52 untreated CLL patients. MRD was assessed in PB every two cycles to facilitate MRD-directed treatment discontinuation after repeated MRD negativity in PB and bone marrow (BM). Importantly, as per the study protocol, all patients were monitored for MRD recurrence and re-started study treatment in the case of MRD detection. With an UM-IGHV and TP53 alterations detectible in 71% and 17% of patients, respectively, adverse prognostic genetic parameters were clearly elevated in the study population. Overall, 96% of the patients achieved MRD negativity in PB, 92% of patients in both PB and BM. Thereby, MRD negativity rates rose from 2% after 2 months to 77.6% after 8 months on treatment. Of interest, a 400-fold reduction in MRD at cycle 5 day 1 (ΔMRD400) was predictive for early MRD negativity and shorter treatment duration (< 8 months). It is noteworthy that UM-IGHV and TP53-altered disease did not appear to delay MRD clearance. All patients treated eventually achieved the prespecified treatment discontinuation criteria and stopped therapy after a median of 10 months. Median MRD-free-survival, calculated from end of treatment until detectible MRD of over 10-4, was nearly 30 months. Herein, early MRD clearance was associated with longer MRD-free survival (not reached vs. 18.1 months, p = 0.003) despite shorter therapy (8 months vs. 15 months, p < 0.001). With a current median follow-up of 40 months (range: 4.1–47.4 months), median PFS has not been reached. In this respect, however, it has to be emphasized that all patients entering retreatment due to MRD recurrence without clinical relapse were censored in the survival analysis. Study treatment was overall well tolerated with no laboratory or clinical tumor lysis syndromes or fatal adverse events observed. The most common all-cause adverse events were dominated by hematotoxicity with higher-grade neutropenia in 23%, all-grade (mostly mild) thrombocytopenia in 56%, and mild anemia in 35% of patients. Low-grade fatigue, diarrhea, bruising, and nausea were observed in 54%, 44%, 44%, and 35% of cases, respectively [8]. With these encouraging results seen in terms of MRD-guided triple re-/treatment with venetoclax, zanubrutinib, and obinutuzumab, the regimen is currently being in explored with ΔMRD400-directed therapy in frontline CLL.

Whereas data on effective and well-tolerated fixed-duration chemotherapy-free treatment options in frontline CLL are steadily growing, prospective evidence on the feasibility of targeted drugs at relapse in CLL patients previously exposed to time-limited targeted drug combinations is still limited.

In the 4‑year follow-up of the phase 2 study CAPTIVATE, 15-month combination treatment with venetoclax and ibrutinib was confirmed to be highly efficient and feasible in a younger treatment-naive CLL population with a median age of 60 years. The 4‑year PFS was 79% for all 159 patients treated, 73% and 63% for those with UM-IGHV (n = 89) and TP53 dysfunction (n = 27), respectively.

Most importantly, of 19 patients having progressed in CAPTIVATE, genetic analysis did not show emerging acquired resistance in terms of novel mutations in the BTKi binding pocket or PLCG2. Hence, these patients then received second-line treatment with ibrutinib for a median treatment duration of 11.1 months; 17 patients are evaluable for response with a remarkable overall response rate (ORR) of 88% (CR = 6.7%, PR = 93.3%; [9]).

Subsequent amendment of the phase 3 MURANO study investigating venetoclax and rituximab (VenR) versus bendamustine-rituximab (BR) in cases of relapsed/refractory CLL facilitated VenR retreatment in 25 patients remaining progression-free for at least 12 months after the first VenR exposure. Most of these patients carried high-risk adverse prognostic markers such as TP53 aberrations (32%), UM-IGHV (88%), and a complex karyotype (44%). Of note, 44% did not achieve MRD negativity at the end of treatment of the main study. With a median follow-up of 33.4 months, the best ORR was 72% (CR = 24%) and PFS was 23.3 months. Median OS has not been reached. Remarkably, eight patients (32%) were negative for MRD after retreatment, all of whom did not achieve MRD clearance after their first exposure to VenR [10].

Taken together, these follow-up data of CAPTIVATE and MURANO suggest that time-limited combination treatment with novel drugs may not typically provoke secondary resistance formation and, hence, facilitate retreatment with previously exposed classes of targeted drugs.