title: Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia.
abstract: T cell prolymphocytic leukemia (T-PLL) is a rare, mature T cell neoplasm with distinct features and an aggressive clinical course. Early relapse and short overall survival are commonplace. Use of the monoclonal anti-CD52 antibody alemtuzumab has improved the rate of complete remission and duration of response to more than 50% and between 6 and 12 months, respectively. Despite this advance, without an allogeneic transplant, resistant relapse is inevitable. We report seven complete and one partial remission in eight patients receiving alemtuzumab and cladribine with or without a histone deacetylase inhibitor. These data show that administration of epigenetic agents can overcome alemtuzumab resistance. We also report epigenetically induced expression of the surface receptor protein CD30 in T-PLL. Subsequent treatment with the anti-CD30 antibody-drug conjugate brentuximab vedotin overcame organ-specific (skin) resistance to alemtuzumab. Our findings demonstrate activity of combination epigenetic and immunotherapy in the incurable illness T-PLL, particularly in the setting of previous alemtuzumab therapy.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine and Penn State Hershey Cancer Institute, Hershey, PA 17033, USA.
authors.forename: Zainul S
authors.initials: ZS
authors.lastname: Hasanali
authors.affiliation: Department of Pathology, St. George's University, True Blue, Grenada.
authors.forename: Bikramajit Singh
authors.initials: BS
authors.lastname: Saroya
authors.affiliation: Department of Medicine/Hematology-Oncology, Pennsylvania State University College of Medicine and Penn State Hershey Cancer Institute, Hershey, PA 17033, USA.
authors.forename: August
authors.initials: A
authors.lastname: Stuart
authors.affiliation: Department of Medicine/Hematology-Oncology, Pennsylvania State University College of Medicine and Penn State Hershey Cancer Institute, Hershey, PA 17033, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Shimko
authors.affiliation: Department of Anatomic Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Juanita
authors.initials: J
authors.lastname: Evans
authors.affiliation: Division of Hematology and Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mithun
authors.initials: M
authors.lastname: Vinod Shah
authors.affiliation: Shaner Cancer Center Mount Nittany Medical Center/Pennsylvania State University, State College, PA 6803, USA.
authors.forename: Kamal
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Violetta V
authors.initials: VV
authors.lastname: Leshchenko
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Parekh
authors.affiliation: Department of Medicine/Hematology-Oncology, UVA Cancer Center, Charlottesville, VA 22903, USA. tploughran@virginia.edu epner5@msn.com.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: Department of Hematology/Oncology, New Mexico VA Health Care System, Albuquerque, NM 87108, USA. tploughran@virginia.edu epner5@msn.com.
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Epner
mesh_terms: D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D000079963:Brentuximab Vedotin; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use; D017730:Ki-1 Antigen / Q000378:metabolism; D015461:Leukemia, Prolymphocytic, T-Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002843:Chromatin; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D000074323:Alemtuzumab; D000079963:Brentuximab Vedotin