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Extended Phase 3 Results From RESONATE-2
years. This extended follow up allowed for new observa- tions into the timing of when AEs occurred and time to resolution of AEs as well as the use of transfusions and growth factors. Diarrhea, while frequent, often occurred early during the first several months of treatment and was generally low grade and short-lived. Severe and treatment- limiting AE rates decreased over time with extended ibru- tinib treatment. A decrease in myelotoxicity and infec- tious complications over time was also observed. This contrasts with chemoimmunotherapy-associated AEs and was importantly associated with less medical resource uti- lization of neutrophil growth factors and slightly less transfusion need despite 4 times the treatment time with ibrutinib. While the rate of atrial fibrillation increased from 6% in the primary analysis13 to 10%, overall, ibruti- nib dose reduction or discontinuation due to atrial fibrilla- tion was uncommon and lessened with extended treat- ment in this population of older patients with CLL. Atrial fibrillation therefore appears manageable and does not fre- quently necessitate ibrutinib discontinuation. Additional information on the management and outcomes of atrial fibrillation along with associated anticoagulant therapy has been provided in a large pooled analysis of ibrutinib studies.28 Rates of major hemorrhage remained low despite half the patients receiving concomitant antiplatelet or anticoagulant medications.
Previous work demonstrated that QOL is significantly compromised in patients with CLL, affecting physical fit- ness, cognitive function, levels of fatigue, and sleep. Worse scores were reported for patients receiving chemotherapy such as chlorambucil.29 Even with the addition of contem- porary anti-CD20 agents (obinutuzumab), no significant benefit in QOL has been noted.4 However, this extended follow up provides the first analysis of QOL, as measured by FACIT Fatigue Scale, following ibrutinib treatment in previously untreated patients. Significantly greater improvements in QOL were observed with ibrutinib versus chlorambucil. In line with this and the favorable impact on QOL and tolerable safety profile, 79% of patients remained on first-line treatment with ibrutinib at the time of this later analysis with up to 3 years of therapy.
Patients who discontinue treatment for CLL including ibrutinib may have varied outcomes dependent on the reason for discontinuation.30 In 1 study that included most- ly patients with relapsed or refractory CLL, median OS following ibrutinib therapy was 33 months for those who discontinued because of AEs versus 16 months for those who discontinued because of disease progression. In our
study, the 22 patients who discontinued therapy had a median follow up of 13 months after discontinuation. Of these 22 patients, 16 are still alive, while 2 of the 4 patients who progressed have died. Seven patients have received subsequent treatment, mostly chemoimmunotherapy (BR, FCR); 6 of those patients are still alive, with a median of 21 months of follow up. While retrospective analyses of real-world data have previously suggested that treatment with an alternate kinase inhibitor is more effective than chemoimmunotherapy following discontinuation of ibru- tinib,31,32 our data suggests that patients who discontinue ibrutinib can respond to chemoimmunotherapy as sec- ond-line therapy. Continued follow up of patients in the RESONATE-2 trial who have discontinued ibrutinib will provide the needed further data as relatively few patients have progressed or stopped therapy to date.
These data confirm that first-line treatment with ibruti- nib results in long-term PFS in patients with CLL and that response quality continues to improve with ibrutinib over time, with substantial increase in patients achieving CR. In addition, rates of grade ≥3 AEs during treatment with ibrutinib decreased over time. The most common reasons for initiating first-line treatment in these patients, includ- ing marrow failure, disease burden, and disease symp- toms, all improved to greater extents in patients treated with ibrutinib versus chemotherapy. Ongoing randomized studies, including ILLUMINATE (clinicaltrials.gov identifier 02264574), comparing ibrutinib-obinutuzumab with chlo- rambucil-obinutuzumab, and A041202 (clinicaltrials.gov identifier 01886872), comparing ibrutinib, ibrutinib-ritux- imab, and rituximab-bendamustine, will continue to define the role of ibrutinib for the first-line treatment of patients with CLL/SLL.
Funding
This study was supported by Pharmacyclics LLC, an AbbVie company, by grants (CA016672 and 5P01CA081534-14) from the National Institutes of Health, and by the MD Anderson Moon Shot Program in CLL. Pharmacyclics LLC, an AbbVie company, sponsored and designed the study. Study investigators and their research teams collected the data. The sponsor con- firmed data accuracy and performed analysis of the data. Medical writing support was funded by the sponsor.
Acknowledgments
We thank all the patients who participated in this trial and their families and Jennifer Leslie, PhD, for medical writing sup- ported by Pharmacyclics LLC, an AbbVie company.
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