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M. Fürstenau et al.
ORR was 88% in the r/r patients and 84% in the treat- ment-naïve cohort while 67% of treatment-naïve patients and 50% of all r/r patients had no detectable MRD in bone marrow and peripheral blood.
The first study successfully using two novel agents that directly target the B-cell receptor pathway combined umbralisib with ibrutinib and produced an ORR of 90% (CR: 29%) and a 2-year PFS of 90%.74 In contrast to prior studies that combined multiple kinase inhibitors, this combination was well-tolerated and no dose-limiting tox- icities were observed. The same combination plus ublitux- imab was assessed safe and active in a phase I study in which the ORR was 100% among 22 previously treated patients with CLL or small lymphocytic lymphoma. The median duration of response was 22.7 months.75
Checkpoint inhibitor monotherapy has shown limited efficacy in CLL but promising activity in Richter transfor- mation.76 A phase II study investigated the combination of ibrutinib and nivolumab in patients with high-risk CLL or Richter transformation.77 While the combination showed promising efficacy in Richter transformation, it produced an ORR of 61% in the high-risk CLL group, which is com- parable to that achieved with single-agent ibrutinib.
Discussion
Ibrutinib monotherapy has produced unprecedented PFS and OS in various groups of CLL patients.3,9,10,13,14 Being the only novel agent that has been broadly approved in the first-line setting, it remains the most widely used novel agent in clinical routine. For the consequently increasing number of patients relapsing after ibrutinib, current evidence indicates that optimal sequencing of novel agents can lead to long PFS and OS with an overall favorable safety profile.39-41,78 The bar in terms of PFS has been raised high by the sequence of frontline ibrutinib fol- lowed by venetoclax.
However, continued monotherapy is associated with some drawbacks including the development of resistance mutations, an increased financial burden, cumulative toxic- ities, and long-term adherence issues.18,19,36,38,45,47,50,79 These fac- tors underscore the need for further development of time- limited treatment concepts that lead to deep and durable remissions, ideally with long treatment-free intervals.
With the broad approval of venetoclax plus rituximab for r/r CLL, a first chemotherapy-free fixed-duration regi- men has pushed into clinical practice and the even shorter combination treatment of venetoclax and obinutuzumab that has proven its striking efficacy in treatment-naïve patients has just followed. Based on the CLL14 data com- paring chlorambucil plus obinutuzumab versus fixed-dura- tion venetoclax plus obinutuzumab for 12 months another venetoclax combination therapy has been approved by the FDA for the frontline treatment of patients with CLL.
The essential question of how durable achieved remis- sions are after stopping combination treatment was in part answered by two recently published long-term follow- ups. In the MURANO trial, the majority of MRD-negative remissions were sustained with a median follow-up of 9.9 months after the end of study treatment.35 Furthermore, Cramer et al. documented that 13 of 17 high-risk CLL patients (17p deletion/TP53 mutation) who achieved undetectable MRD after a time-limited treatment with either venetoclax plus obinutuzumab or ibrutinib plus
obinutuzumab had ongoing remissions after a median observation time of 16 months after the end of study treatment.68
While these treatment-free phases are certainly desir- able from a patient’s point of view, their effect on clonal evolution of CLL remains largely unknown. It is conceiv- able though that shorter exposure to ibrutinib and veneto- clax might be associated with a lower incidence of drug- specific resistance mutations as most of these seem to appear later in the course of monotherapy.16,18,37,38,47,80,81 The absence of resistance mutations and treatment-free inter- vals could allow for re-exposure of patients to the same combination treatment, potentially with a similar efficacy as before.
Comprehensive safety analyses are much needed, par- ticularly in the context of novel-novel combinations to detect treatment-specific toxicities that might not be detected in smaller phase II trials.27,36,82 As ibrutinib alone seems to be associated with an increased incidence of cer- tain opportunistic infections, it is conceivable that this specific risk might be even higher when this drug is com- bined with additional substances that influence the immune system.83,84
Detailed pharmacokinetic analyses are also warranted to optimize combination treatments as kinase inhibitors and venetoclax might interact due to their CYP-dependent metabolism.85 A recent study found that even reduced doses of ibrutinib lead to complete BTK occupancy, possi- bly clearing the way for lower dosed treatment with fewer off-target effects.17
Results from the currently recruiting phase III FLAIR (2013-001944-76) and GAIA/CLL13 (NCT02950051) trials are eagerly awaited to see whether time-limited combina- tions of novel agents prove themselves superior in a direct comparison with standard first-line regimens. While the GAIA/CLL13 trial is investigating various venetoclax- based combinations in young and fit patients, the FLAIR study will show, in a similar group of patients, whether the promising oral combination of ibrutinib plus veneto- clax is superior to the current standards, ibrutinib monotherapy and fludarabine, cyclophosphamide and rit- uximab.
However, it will probably take more well-designed, ran- domized trials and particularly long-term follow-up data as well as detailed analyses of PFS2 or 3 after combination treatments in order to determine conclusively whether sequential single-agent therapy or novel combination ther- apy is superior to the other.
With upcoming combination therapies in contrast to continuous monotherapies, the optimal selection of indi- vidual treatment for each patient is challenging. For instance, patients with a complex karyotype who might be more susceptible to the development of resistance mutations under single-agent monotherapy could be eligi- ble for novel combinations.86 Ahn and colleagues recently presented a risk score that predicts survival and the occur- rence of resistance mutations in the context of ibrutinib monotherapy, whereas Visentin and colleagues developed a score that predicts atrial fibrillation during ibrutinib treatment.17,87 These are just two examples of how more available information will lead to a further diversification and personalization of treatment options. It is, therefore, crucial to work on identifying additional risk factors and understanding disease biology and clonal evolution of CLL in the context of novel agents.
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