Before the era of targeted agents, chemoimmunotherapy (CIT) was the standard frontline treatment option for patients with newly diagnosed chronic lymphocytic leukemia (CLL). Recently, the standard of care in this setting has shifted from CIT to targeted agents. New agents targeting BTK or BCL-2, either alone or in combination with a CD20 antibody, demonstrated superiority to CIT as frontline therapy for CLL in multiple phase III trials.^1-4

The BTK inhibitor ibrutinib received approval from the FDA in 2016 for treating newly diagnosed CLL based on data from the phase III RESONATE-2 trial comparing ibrutinib with chlorambucil.⁵ Recently, results from 3 phase III trials of ibrutinib-based regimens vs CIT as frontline CLL treatment were published.^1-3 In the E1912 trial, ibrutinib plus rituximab significantly improved PFS and OS compared with fludarabine/cyclophosphamide/rituximab (FCR) in younger patients (aged 70 years or younger) with previously untreated CLL.¹ The A041202 trial was a 3-arm study comparing ibrutinib alone or ibrutinib plus rituximab with bendamustine plus rituximab (BR) in older patients (aged 65 years or older) with previously untreated CLL.² Results from this trial demonstrated that both ibrutinib alone and ibrutinib plus rituximab significantly improved PFS compared with BR regardless of the presence of high-risk cytogenetics such as del(17p). However, there was no PFS difference between the 2 ibrutinib-containing arms. Finally, the iLLUMINATE trial comparing ibrutinib plus obinutuzumab, another anti-CD20 antibody, with chlorambucil plus obinutuzumab in older (aged 65 years or older) or unfit patients with previously untreated CLL met its primary endpoint of significantly improved PFS.³ In this study, the PFS benefit with ibrutinib was observed across all patient subgroups including the high-risk patient population with del(17p). Taken together, all 3 trials showed that ibrutinib, either as monotherapy or combined with a CD20 antibody, substantially prolonged PFS compared with standard-of-care CIT regimens as frontline therapy for CLL regardless of patient age, fitness, or cytogenetics. Notably, results from the A041202 trial suggested that adding rituximab to ibrutinib does not provide additional PFS benefit, and currently, it is unclear whether combining ibrutinib with obinutuzumab is better than ibrutinib monotherapy as the iLLUMINATE trial did not address this question directly. Although the FDA approved the combination of ibrutinib plus obinutuzumab in January 2019 as frontline treatment for CLL based on the iLLUMINATE data, many experts in CLL prefer to use ibrutinib as a single agent instead of in combination with obinutuzumab. Results from the ongoing phase III ELEVATE-TN trial should shed more light on the role of obinutuzumab when combined with a BTK inhibitor in previously untreated CLL. This 3-arm trial is assessing the second-generation BTK inhibitor acalabrutinib alone vs acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab as frontline therapy for patients with previously untreated CLL. In June 2019, a press release announced that the ELEVATE-TN trial met its primary endpoint of improved PFS at the interim analysis; full results from this trial are expected to be presented later this year.

Venetoclax is a BCL-2 inhibitor that was originally approved in 2016 as a monotherapy for patients with previously treated CLL and del(17p). In May 2019, the FDA approved venetoclax in combination with obinutuzumab as frontline therapy for CLL based on results from the phase III CLL14 trial.⁴ In this trial, previously untreated patients with CLL and coexisting medical conditions received either venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab with both regimens given for a fixed duration. The primary endpoint of PFS was significantly longer in the venetoclax plus obinutuzumab arm vs the control arm of chlorambucil plus obinutuzumab, and the PFS benefit with venetoclax was observed regardless of del(17p) and/or TP53 mutation status. In addition, the incidence of detectable measurable residual disease (MRD) was significantly lower in patients receiving venetoclax plus obinutuzumab compared with those who received chlorambucil plus obinutuzumab. The role of MRD negativity (ie, the absence of detectable MRD) is becoming more important in CLL because it is associated with long-term clinical benefits even with fixed-duration therapy.⁶ In comparison, ibrutinib-based regimens typically do not yield high MRD negativity rates, and patients remain on therapy indefinitely if there are no tolerability issues. The CLL14 trial has established venetoclax plus obinutuzumab as another chemotherapy-free regimen in patients with previously untreated CLL including high-risk disease with the advantage of being a fixed-duration therapy. The choice between ibrutinib or venetoclax plus obinutuzumab for individual patients with newly diagnosed CLL requiring treatment will depend on factors such as the respective toxicity profiles and patient comorbidities, dosing schedule, drug–drug interactions, and financial considerations.

Beyond these new chemotherapy-free standards of care, multiple phase III trials are currently investigating novel agents and combinations in patients with newly diagnosed CLL. For example, the combination of venetoclax and a BTK inhibitor with or without obinutuzumab is being examined as frontline therapy in several trials including the phase III ACE-CL-311 and CLL13 trials. The 3-arm ACE-CL-311 trial is comparing venetoclax plus acalabrutinib with or without obinutuzumab with standard CIT in patients with previously untreated CLL with no del(17p) or TP53 mutation. The CLL13 trial is a 4-arm trial comparing 3 separate venetoclax-based regimens (venetoclax plus rituximab, venetoclax plus obinutuzumab, or venetoclax plus ibrutinib and obinutuzumab) to CIT such as FCR or BR in the same patient population as ACE-CL-311. Results from these studies have the potential to further improve the care of patients with newly diagnosed CLL.

More information on the evolving management of patients with CLL is available from various online educational sources such as Clinical Care Options.