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Novel agents in CLL
limited duration, achieve deep and long-lasting remis- sions. The only approved treatment concepts that meet these criteria and show a favorable safety profile are the 24-month fixed-duration combination of venetoclax and rituximab and the 12-month fixed-duration combination of venetoclax and obinutuzumab.31 A multitude of differ- ent combination treatments containing novel agents are currently being investigated.
Undetectable minimal residual disease as a treatment goal of new combination therapies
In 2016, the European Medicines Agency accepted the use of undetectable MRD as a surrogate for PFS and as an intermediate endpoint in CLL trials. This decision was based on large analyses of chemoimmunotherapy studies that demonstrated a strong association between MRD sta- tus and PFS and established undetectable MRD as an inde- pendent prognostic factor for PFS and OS.34,51-55 Recently the predictive value of undetectable MRD was confirmed in the context of treatment with several new substances.
An analysis of venetoclax monotherapy showed that 2- year PFS rates were significantly higher in patients who achieved undetectable (<10-4) or intermediate MRD (≥10-4 to <10-2) than in patients who never achieved MRD <10-2 (92.8%, 84.3%, and 63.2%, respectively).33 Similarly, the recently published follow-up of the MURANO study underscored the predictive value of MRD status in the context of venetoclax plus rituximab treatment.35 In con-
trast, the complete remission rate with ibrutinib monotherapy increased with a significant delay over time and reached 28% after a median time of 60 months. Undetectable MRD is still rarely achieved and in clinical trials evaluating ibrutinib therapy no correlation between MRD status and survival has been established so far.16
Since low MRD levels promise longer PFS and, presum- ably, treatment-free survival, the achievement of the low- est possible MRD level represents a desirable treatment goal. With chemoimmunotherapy the eradication of MRD below the detection limit of one CLL cell per 10,000 nor- mal leukocytes (<10-4) could only be reliably achieved by intensive treatment regimens (e.g. fludarabine, cyclophos- phamide and rituximab), which were not tolerable for the majority of elderly CLL patients with comorbidities.1,2 With the increasing availability of new substances, high rates of MRD-negative CR can also be achieved in older patients with comorbidities (Table 1).
Combinations
Chemoimmunotherapy plus novel agents
As undetectable MRD and CR are not commonly achieved with ibrutinib alone, several studies have com- bined the BTK inhibitor with chemoimmunotherapy to increase efficacy (Table 2). In the recently published fol- low-up of the HELIOS trial evaluating ibrutinib together
Figure 2. Proposed algorithm for first-line treat- ment using approved options in clinical practice. y: years; R: rituximab; FCR: fluradabine, cyclophosphamide, rituximab; BR: bendamustine, rituximab; Clb-G: chlorambucil, obinutuzumab.
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