title: Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes.
abstract: BACKGROUND
  Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown.
  
  
  METHODS
  We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study.
  
  
  RESULTS
  We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS.
  
  
  CONCLUSIONS
  The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Cheah
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: D
authors.initials: D
authors.lastname: Chihara
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Romaguera
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Fowler
authors.affiliation: Department of Haematology, Peter MacCallum Cancer Center, Melbourne; Department of Haematology, University of Melbourne, Melbourne, Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Seymour
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: F B
authors.initials: FB
authors.lastname: Hagemeister
authors.affiliation: Department of Stem Cell Transplantation, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Champlin
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: miwang@mdanderson.org.
authors.forename: M L
authors.initials: ML
authors.lastname: Wang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D057915:Drug Substitution; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000097:blood; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010880:Piperidines; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012189:Retrospective Studies; D012307:Risk Factors; D016879:Salvage Therapy / Q000009:adverse effects; D013781:Texas; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D007770:L-Lactate Dehydrogenase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine
keywords: Bruton's tyrosine kinase inhibitors; ibrutinib; mantle cell lymphoma; prognosis; treatment