title: Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial.
abstract: BACKGROUND
  Patients with relapsed or refractory peripheral T-cell lymphoma have a poor prognosis after conventional chemotherapy. Approved novel agents have only modest single-agent activity in most subtypes of peripheral T-cell lymphoma. Panobinostat is a potent oral pan-deacetylase inhibitor. Findings of many preclinical studies have shown synergistic antilymphoma activity when panobinostat is combined with the proteasome inhibitor bortezomib. We aimed to study the effect of panobinostat and bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma.
  
  
  METHODS
  In this open-label, multicentre phase 2 trial, we recruited patients aged 21 years or older with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy from five tertiary hospitals in Singapore, Malaysia, and South Korea. Patients received 20 mg oral panobinostat three times a week and 1·3 mg/m(2) intravenous bortezomib two times a week, both for 2 of 3 weeks for up to eight cycles. The primary endpoint was the proportion of patients who achieved an objective response in accordance with the International Working Group revised response criteria; analyses were by intention to treat. The study is completed and is registered with ClinicalTrials.gov, number NCT00901147.
  
  
  RESULTS
  Between Nov 9, 2009, and Nov 26, 2013, we enrolled 25 patients with various histological subtypes of peripheral T-cell lymphoma. Of 23 patients assessable for responses, ten (43%, 95% CI 23-63) patients had an objective response, of which five were complete responses. Serious adverse events were reported in ten (40%) of 25 patients. Common treatment-related grade 3-4 adverse events included thrombocytopenia (17 [68%]), neutropenia (ten [40%]), diarrhoea (five [20%]), and asthenia or fatigue (two [8%]). We recorded peripheral neuropathy of any grade in ten (40%) patients.
  
  
  CONCLUSIONS
  Combined proteasome and histone deacetylase inhibition is safe and feasible and shows encouraging activity for patients with peripheral T-cell lymphoma. Our findings validate those of preclinical studies showing synergism in the combination and represent a rational way forward in harnessing the full potential of novel agents in peripheral T-cell lymphoma.
  
  
  BACKGROUND
  Novartis Pharmaceuticals, Janssen Pharmaceuticals, and Singhealth Foundation.
authors.affiliation: Department of Hematology, Singapore General Hospital, Singapore; Raffles Cancer Centre, Raffles Hospital, Singapore.
authors.forename: Daryl
authors.initials: D
authors.lastname: Tan
authors.affiliation: Department of Hematology, Singapore General Hospital, Singapore.
authors.forename: Colin
authors.initials: C
authors.lastname: Phipps
authors.affiliation: Department of Hematology, Singapore General Hospital, Singapore.
authors.forename: William Y K
authors.initials: WY
authors.lastname: Hwang
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Department of Hematology, Singapore General Hospital, Singapore.
authors.forename: Chun Hsien
authors.initials: CH
authors.lastname: Yeap
authors.affiliation: Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yiong Huak
authors.initials: YH
authors.lastname: Chan
authors.affiliation: Medical Oncology, National Cancer Centre of Singapore, Singapore.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tay
authors.affiliation: Medical Oncology, National Cancer Centre of Singapore, Singapore.
authors.forename: Soon Thye
authors.initials: ST
authors.lastname: Lim
authors.affiliation: Department of Hematology, Singapore General Hospital, Singapore.
authors.forename: Yuh Shan
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Hematology, Singapore General Hospital, Singapore.
authors.forename: Sathish Gopalakrishnan
authors.initials: SG
authors.lastname: Kumar
authors.affiliation: Sime Darby Medical Centre, Selangor, Malaysia.
authors.forename: Soo Chin
authors.initials: SC
authors.lastname: Ng
authors.affiliation: Hospital Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
authors.forename: S
authors.initials: S
authors.lastname: Fadilah
authors.affiliation: Samsung Medical Centre, Seoul, South Korea.
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Hematology, Singapore General Hospital, Singapore. Electronic address: goh.yeow.tee@sgh.com.sg.
authors.forename: Yeow Tee
authors.initials: YT
authors.lastname: Goh
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000069286:Bortezomib / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy*; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077767:Panobinostat; D056910:Republic of Korea; D012846:Singapore; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D007211:Indoles; D000069286:Bortezomib; D000077767:Panobinostat