title: Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Kami J
authors.initials: KJ
authors.lastname: Maddocks
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.affiliation: Department of Pathology, The Ohio State University, Columbus.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.affiliation: Department of Pathology, The Ohio State University, Columbus.
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Department of Pathology, The Ohio State University, Columbus.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pathology, The Ohio State University, Columbus.
authors.forename: Lynne
authors.initials: L
authors.lastname: Abruzzo
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Arletta
authors.initials: A
authors.lastname: Lozanski
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Melanie
authors.initials: M
authors.lastname: Davis
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Amber
authors.initials: A
authors.lastname: Gordon
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Rose
authors.initials: R
authors.lastname: Mantel
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Jaglowski
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Farrukh
authors.initials: F
authors.lastname: Awan
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002986:Clinical Trials as Topic; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009820:Ohio; D051966:Phospholipase C gamma / Q000235:genetics; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051966:Phospholipase C gamma; D000225:Adenine