Back Back
CLL Treatment Revolution
The CLL Treatment Revolution

Released: May 26, 2015

Expiration: May 24, 2016

Activity Information

Activity

Progress
1
Course Completed
Continue

Management of relapsed chronic lymphocytic leukemia (CLL) has undergone a revolution in the past year, following the FDA approval of the BTK inhibitor ibrutinib, the PI3K inhibitor idelalisib, and the anti-CD20 antibody obinutuzumab. Venetoclax (ABT-199), an oral BCL-2 inhibitor, has substantial activity in this setting with very promising results in early trials, and it recently received a Breakthrough Therapy designation from the FDA for patients with relapsed/refractory CLL and the 17p deletion, making it likely that it will gain approval soon. With several BTK (CC-292, ONO-499) and PI3K (duvelisib/IPI-145) inhibitors in late-phase clinical trials, and additional therapies such as CAR T-cell therapy (CTL019, CD19CAR-28-zeta T cells, ROR1R-CAR-T cells) under investigation, clinicians will have more options than ever before for managing relapsed CLL.

Although patients will likely benefit from the availability of such therapies, many clinicians are likely to be confused by the multitude of clinically available options. Furthermore, novel combination strategies will make such choices exponentially more challenging.

Treatment Selection in Relapsed CLL
The key determinants for therapy selection in relapsed CLL include response to initial therapy, patient performance status, and specific comorbidities. Although both idelalisib and ibrutinib have broad indications in the relapsed setting, continued chemoimmunotherapy may remain appropriate for the subset of patients who have a long response to initial chemoimmunotherapy and who have not developed clonal evolution with the acquisition of chemotherapy resistance markers such as deletions of 17p/11q or mutations in TP53, SF3B1, or NOTCH1. In 2 recent studies, rates of TP53 mutations and/or 17p/11q deletions were as high as 50%. Unfortunately, many clinicians are unfamiliar with such markers and how to integrate such results into clinical practice and may continue treating with chemoimmunotherapy when the available data indicate that their patients may benefit more from approved targeted agents.

Ibrutinib and Idelalisib
Ibrutinib is the first approved agent that targets B-cell receptor signaling in CLL. Ibrutinib was approved by the FDA in 2014 for the treatment of patients with CLL who have progressed on at least 1 previous therapy, as well as for the treatment of patients with CLL and del(17p). In the phase III RESONATE trial, progression-free survival and overall response rate were significantly improved with ibrutinib vs ofatumumab regardless of baseline genetics (del17p, del11q), genetic mutations (eg, SF3B1, NOTCH1), complex karyotype, or number of previous therapies, and overall survival was significantly superior in the ibrutinib group as well. The remarkable efficacy of ibrutinib and its favorable toxicity profile have resulted in rapid incorporation into clinical practice.

However, it is notable that 25% patients (14.6% nonrelapse related) in clinical trials of ibrutinib at Ohio State University and 26% in a study at M. D. Anderson Cancer Center discontinued therapy. Acquired mutations in BTK and PLCG2 account for most CLL progressions during ibrutinib therapy and patients with CLL progression tended to have rapid disease progression following discontinuation.

Idelalisib was also approved in 2014 in combination with rituximab for patients with relapsed CLL. The combination demonstrated profound improvements in progression-free survival and overall survival vs rituximab monotherapy in a phase III trial, including in patients with del(17p)/TP53 mutation. In a subanalysis, patients with del(17p)/TP53 mutation treated with idelalisib plus rituximab showed significantly improved overall survival vs those treated with rituximab plus placebo (not reached vs 14.8 months, respectively; HR: 0.31; 95% CI: 0.15-0.65; P = .01). However, utilization by clinicians has been considerably less than for ibrutinib. This may be partially related to the unique adverse effect profile of idelalisib, including severe liver function test abnormalities, diarrhea, and colitis.

Many physicians may be uncertain how to select between ibrutinib and idelalisib. It is not yet known which agent is more effective in patients with relapsed CLL, as head-to-head studies have not been performed. Furthermore, the registration studies evaluated significantly different patient populations, rendering cross-trial comparisons difficult. The population in the study leading to approval of idelalisib, for example, was older and had significantly more comorbidities than those in the study that led to approval of ibrutinib. Ibrutinib clinical trials show that a majority of patients will tolerate the drug very well; however, older age has been shown to be most significant variable for drug discontinuation. Ibrutinib is associated with bleeding complications and has not been extensively characterized in the setting of therapeutic anticoagulation.

Patients with ibrutinib-treated CLL with the 17p deletion may have less favorable outcomes compared with patients lacking 17p deletion. By contrast, 17p deletions have no impact on outcome of patients treated with idelalisib. Despite these differences, it remains unclear which agent is more effective in this setting.

Novel agents have transformed the clinical management of CLL. With multiple pivotal trials of an array of novel agents set to report outcomes in the next few years, CLL treatment is positioned for accelerating advances. Becoming familiar with the risks and benefits of ibrutinib, idelalisib, and other novel agents is essential in providing optimal patient care.

Your Thoughts?
What agent or agents do you prefer to use for your patients with relapsed CLL? Why? Let us know with your comments below and in the poll question on this page.

Continue

Poll

1.
In your current practice, which of the following do you use most often to treat patients with relapsed/refractory CLL and a del(17p) mutation?
Submit