Prognostic Factors for Complete Response to Ibrutinib in Patients With Chronic Lymphocytic Leukemia: A Pooled Analysis of 2 Clinical Trials

Abstract

Importance: Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor taken once daily, is approved in the United States for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and allows for treatment without chemotherapy. Extended treatment with ibrutinib has demonstrated increased complete response (CR) rates over time.

Objective: To analyze baseline factors that predict CR in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with ibrutinib.

Design, setting, and participants: Univariate and multivariate analyses of pooled data from 2 clinical trials were used to assess the prognostic value of baseline factors associated with CR in 327 patients from the PCYC-1102 and PCYC-1112 studies treated with single-agent ibrutinib. Participants were followed up in academic and community medical centers in the United States, the United Kingdom, Australia, France, Italy, Ireland, Poland, Spain, and Austria.

Main outcomes and measures: Odds ratio (OR) of CR rate.

Results: The 327 patients included in this analysis had a median age of 67 years (range, 30-86 years) and 227 (69.4%) were male. At baseline, 185 patients (56.6%) had bulky disease (lymph node ≥5 cm), 184 (56.3%) had advanced-stage disease, and 182 (55.7%) had an Eastern Cooperative Oncology Group performance status of 1 or higher. Thirty-one patients (9.5%) were in the first-line setting; 38 (11.6%) had undergone 1 previous therapy, 81 (24.8%) had undergone 2, and 177 (54.1%) had undergone 3 or more; patients with relapsed/refractory disease had undergone a median of 3 (range, 0-12) previous therapies. Median time on study was 26.4 months (range, 0.3-55.6 months). Thirty-two of the 327 patients (9.8%) treated with ibrutinib had a CR (PCYC-1102: relapsed/refractory, 12 of 101 [11.9%]; treatment-naive, 8 of 31 [25.8%]; and PCYC-1112: 12 of 195 [6.2%]). The median time to CR for these patients was 14.7 months (range, 4.6-47.1 months). Univariate analysis of baseline factors showed that bulky disease, clinical stage, number of previous therapies, and β2-microglobulin concentration had a significant effect on the odds of CR. The final multivariate model showed that patients with no previous therapy vs patients with at least 1 previous therapy (OR, 2.65; 95% CI, 1.01-6.95; P = .047) and patients without bulky disease (lymph node <5 cm) vs those with bulky disease (lymph node ≥5 cm [OR, 4.97; 95% CI, 1.91-12.91; P = .001]) had an increased likelihood of CR.

Conclusions and relevance: Patients receiving ibrutinib as a first-line therapy for chronic lymphocytic leukemia and those without bulky disease had a better likelihood of CR to treatment. The CR rate with continued longer-term ibrutinib treatment was higher than in previous reports.

Trial registration: clinicaltrials.gov Identifiers: NCT01105247 and NCT01578707.

Conflict of interest statement

Conflict of Interest Disclosures: Dr O’Brien reported receiving research funding from Pharmacyclics LLC, an AbbVie Company, and consulting and advisory fees and honoraria from AbbVie, Janssen, and Pharmacyclics LLC, an AbbVie Company. Dr Jaglowski reported receiving consulting fees and research funding from Pharmacyclics LLC, an AbbVie Company. Dr Byrd reported receiving research funding from Genentech, Acerta Pharma, and Pharmacyclics LLC, an AbbVie Company. Dr Bannerji reported that his spouse was employed by ID Care and reported receiving research funding from AbbVie, Gilead Sciences Inc, Regeneron Pharmaceuticals, Roche-Genentech, Merck, MedImmune, and Pharmacyclics LLC, an AbbVie Company; having a patent with Merck; and receiving travel accommodations from Regeneron Pharmaceuticals and Merck. Dr Blum reported receiving research funding from Celgene, Novartis, Janssen Pharmaceuticals, Seattle Genetics, Millennium Pharmaceuticals, Gilead Sciences Inc, MorphoSys AG, Constellation Pharmaceuticals and Pharmacyclics LLC, an AbbVie Company. Dr Fox reported receiving honoraria, consultancy fees, travel accommodations, and research funding from Roche, AbbVie, and Gilead Sciences Inc; honoraria, consultancy fees, and travel accommodations from Janssen Pharmaceuticals and Takeda Pharmaceuticals; honoraria, consultancy fees, and research funding from ADIENNE; and honoraria and consulting fees from Celgene. Dr Furman reported receiving honoraria, travel accommodations, and consulting fees from AbbVie and Pharmacyclics LLC, an AbbVie Company, and serving in a paid position on the speakers’ bureau of Pharmacyclics LLC, an AbbVie Company. Dr Hillmen reported serving on the speakers’ bureau and receiving honoraria and consulting fees from AbbVie, Janssen Pharmaceuticals, Gilead Sciences Inc, and Acerta Pharma and receiving research funding from AbbVie and Pharmacyclics LLC, an AbbVie Company. Dr Kipps reported receiving consulting fees and research funding from AbbVie, Genentech, and Pharmacyclics LLC, an AbbVie Company; consulting fees from Gilead Sciences Inc; and research funding from Oncternal Therapeutics. Dr Montillo reported receiving honoraria and consulting fees from Roche, Gilead Sciences Inc, and Janssen Pharmaceuticals and honoraria from Novartis. Dr Sharman reported receiving honoraria, consulting fees, and research funding from Gilead Sciences Inc, Acerta Pharma, Celgene and Pharmacyclics LLC, an AbbVie Company, and consulting fees and research funding from Genentech. Mr Suzuki reported employment and equity ownership in Iovance Biotherapeutics Inc and serving as a paid consultant and advisor for Pharmacyclics LLC, an AbbVie Company. Dr James reported employment with Pharmacyclics LLC, an AbbVie Company, and holding equity ownership in, having patents with, and receiving other royalties from AbbVie. Dr Chu reported employment with Pharmacyclics LLC, an AbbVie Company, and holding equity ownership in AbbVie. Dr Coutre reported receiving consulting fees from Janssen Pharmaceuticals and consulting fees and research funding from AbbVie, Gilead Sciences Inc, Novartis, Celgene, and Pharmacyclics LLC, an AbbVie Company. No other disclosures were reported.

Figures

Figure.. Overall Response Rate (ORR) and Complete Response (CR) Rate Over Time in 327 Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated With Ibrutinib

At up to 48 months of follow-up, patients with CLL/SLL (N = 327) had an 89.6% ORR from 21 months onward and a time-dependent improvement in CR rate with continued once-daily ibrutinib therapy. CRi indicates CR with incomplete bone marrow recovery.