Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol 2015 Apr;1(1):80-7
Date
07/17/2015Pubmed ID
26182309Pubmed Central ID
PMC4520535DOI
10.1001/jamaoncol.2014.218Scopus ID
2-s2.0-84994504370 (requires institutional sign-in at Scopus site) 478 CitationsAbstract
IMPORTANCE: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up.
OBJECTIVE: To determine features associated with discontinuation of ibrutinib therapy and outcomes.
DESIGN, SETTING, AND PARTICIPANTS: A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014.
MAIN OUTCOMES AND MEASURES: Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse.
RESULTS: With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient.
CONCLUSIONS AND RELEVANCE: This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not.
TRIAL REGISTRATIONS: clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.
Author List
Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Lozanski A, Davis M, Gordon A, Smith LL, Mantel R, Jones JA, Flynn JM, Jaglowski SM, Andritsos LA, Awan F, Blum KA, Grever MR, Johnson AJ, Byrd JC, Woyach JAAuthor
Samantha M. Jaglowski MD, MPH Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenineAdult
Aged
Aged, 80 and over
Biomarkers, Tumor
Clinical Trials as Topic
DNA Mutational Analysis
Disease Progression
Female
High-Throughput Nucleotide Sequencing
Humans
Kaplan-Meier Estimate
Leukemia, Lymphocytic, Chronic, B-Cell
Male
Middle Aged
Molecular Targeted Therapy
Mutation
Ohio
Phospholipase C gamma
Piperidines
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Pyrazoles
Pyrimidines
Recurrence
Risk Factors
Time Factors
Treatment Outcome
