LAUSR

The treatment landscape for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has evolved from single-agent/combination chemotherapies to anti-CD20 antibody-containing regimens, including chemoimmunotherapy, to novel agents targeting the B-cell receptor signaling pathway or BCL2. In older or less fit patients with comorbidities, standard first-line treatments include chlorambucil combined with anti-CD20 antibodies or single-agent ibrutinib. In the CLL11 study, chlorambucil-obinutuzumab showed superior efficacy compared with chlorambucil or chlorambucil-rituximab in patients with previously untreated CLL and comorbidities. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton tyrosine kinase, is approved in the USA and Europe for the treatment of patients with CLL and allows for treatment without chemotherapy. In the ongoing RESONATE-2 phase III study (PCYC-1115/1116) in CLL/SLL, single-agent, first-line ibrutinib significantly improved progression-free survival (PFS), overall survival, and overall response rate compared with chlorambucil. Recently published results from the iLLUMINATE (PCYC-1130) phase III study showed superior PFS with first-line ibrutinib-obinutuzumab than with chlorambucil-obinutuzumab in patients with CLL/SLL, including patients with high-risk features [del(17p)/TP53mutation, del(11q), and/or unmutated IGHV]. Results of additional randomized studies evaluating single-agent ibrutinib versus standard chemoimmunotherapy regimens in first-line CLL were published recently: in the Alliance Intergroup (A041202) phase III trial, it was found that ibrutinib as a single agent or in combination with rituximab resulted in superior PFS compared with bendamustine-rituximab. However, to date, there are no data comparing single-agent ibrutinib with obinutuzumab-containing regimens. We performed a prespecified cross-trial analysis of the RESONATE-2 and iLLUMINATE studies to compare outcomes with singleagent ibrutinib versus chlorambucil-obinutuzumab. Clinical trial registration: NCT01578707 and NCT02264574 This cross-trial analysis included all patients in the ibrutinib arm from RESONATE-2 and patients without del(17p) from iLLUMINATE, given the exclusion of patients with del(17p) from RESONATE-2. Full details of the study design and eligibility criteria for both studies are described elsewhere and are summarized briefly in the Online Supplemental Methods. The primary analysis was investigator-assessed PFS of patients treated with single-agent ibrutinib in RESONATE-2 versus PFS of patients treated with chlorambucil-obinutuzumab in iLLUMINATE. Secondary analyses included investigator-assessed PFS in genomic high-risk patients [those with TP53 mutation, del(11q), and/or unmutated IGHV], and medical resource utilization during the first 6 months on study treatment. The safety analysis included evaluation of adverse events collected for the time-matched analysis (first 6 months of study treatment) and for the entire follow-up. An exploratory analysis was conducted for single-agent ibrutinib (RESONATE-2) versus ibrutinib-obinutuzumab (iLLUMINATE). This analysis comprised investigatorassessed overall response rate, including complete response; development of lymphocytosis [absolute lymphocyte count (ALC) increased ≥50% from baseline to ≥5x10/L], duration and resolution of lymphocytosis (ALC decreased to baseline level or lower or <5x10/L); and time to normalization of ALC (<4x10/L). Details of the statistical analysis are included in the Online Supplement.