Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience

Abstract

We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade ≥3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069.

Conflict of interest statement

Conflict-of-interest disclosure: S.O. holds a consultancy/advisory role and received honoraria from AbbVie, Janssen, and Pharmacyclics LLC, an AbbVie Company, and received research funding from Pharmacyclics LLC, an AbbVie Company. R.R.F. received honoraria, holds a consultancy/advisory role, and received travel accommodations and expenses from Pharmacyclics LLC, an AbbVie Company and AbbVie, and served on a speakers bureau for Pharmacyclics LLC, an AbbVie Company. S.C. holds a consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, AbbVie, Gilead, Novartis, Janssen, and Celgene, and received research funding from Gilead, Celgene, Novartis, AbbVie, and Pharmacyclics LLC, an AbbVie Company. I.W.F. received research funding from Genentech, Janssen, and Pharmacyclics LLC, an AbbVie Company. J.A.B. received honoraria, holds a consultancy/advisory role and received travel accommodations and expenses from Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, Novartis, and Janssen, and received research funding from Pharmacyclics LLC, an AbbVie Company. K.B. received research funding from Celgene, Novartis, Janssen, Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Millennium, Gilead, Morphosys, and Constellation Pharmaceutical. J.S. holds a consultancy/advisory role and received research funding from Gilead, Pharmacyclics LLC, an AbbVie Company, Celgene, AbbVie, Genentech, Acerta, and TG Therapeutics. W.W. received honoraria from Sanofi, Genentech/Roche, Pharmacyclics LLC, an AbbVie Company, Celgene, Gilead, GSK/Novartis, Genzyme, Merck, AbbVie, and Emergent; received research funding from GSK/Novartis, AbbVie, Genentech, Karyopharm, Pharmacyclics LLC, an AbbVie Company, Acerta, Gilead, Janssen, Emergent, Juno, and Kite; and holds a consulting/advisory role with Sanofi, Genentech/Roche, Pharmacyclics LLC, an AbbVie Company, Celgene, Gilead, GSK/Novartis, Genzyme, Merck, AbbVie, and Emergent. J.J. is employed with Celgene; received honoraria from Janssen and Acerta; holds a consultancy/advisory role with Pharmacyclics LLC, an AbbVie Company, Janssen, AbbVie, Morphosys, and Gilead; and received research funding from Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, Genentech, Gilead, and Acerta. Y.L. is employed with Pharmacyclics LLC, an AbbVie Company; holds stock ownership with AbbVie; and has received travel accommodations and expenses from Pharmacyclics LLC, an AbbVie Company. D.F.J. is employed with Pharmacyclics LLC, an AbbVie Company; holds stock ownership with AbbVie; and has patents with AbbVie. A.D.C. is employed with Pharmacyclics LLC, an AbbVie Company, and holds stock ownership with AbbVie. J.C.B. received research funding from Genentech, Acerta, and Pharmacyclics LLC, an AbbVie Company. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Onset of common grade ≥3 adverse events (in >3% of all treated patients) over time.

Figure 2.

Outcomes in TN and R/R populations. (A) Cumulative best response in TN patients over time. (B) PFS in TN and R/R patients. (C) OS in TN and R/R patients. One TN patient with disease progression on day 2274 was excluded because of the very limited numbers at risk at that time and to ensure appropriate calculation of median. The patient was censored at last response assessment before progression. CRi, CR with incomplete marrow recovery.

Figure 3.

Outcomes in R/R patients with chromosomal abnormalities detected by FISH and with CK. (A) Best response by high-risk genetic features. (B) PFS by chromosomal abnormalities detected by FISH. (C) OS by chromosomal abnormalities detected by FISH. (D) PFS by CK. (E) OS by CK. Survival analysis by FISH cytogenetic subgroups was based on Döhner hierarchy categorization.

Figure 4.

Outcomes in R/R patients by IGHV gene mutation status. (A) PFS by IGHV mutational status. (B) OS by IGHV mutational status.

Figure 5.

Outcomes by prior lines of therapy. (A) PFS by prior lines of therapy. (B) OS by prior lines of therapy.

Figure 6.

Outcomes in R/R patients with CK by presence of del(17p). (A) PFS by del(17p) in R/R patients with CK. (B) OS by del(17p) in R/R patients with CK.