title: A phase 2 trial of combination therapy with thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid (TADA) in patients with overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) or primary myelofibrosis (PMF).
abstract: BACKGROUND
  Primary myelofibrosis (PMF) and overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities, such as the Janus kinase 2 (JAK2) valine to phenylalanine mutation at codon 617 (V617F) and the tet methylcytosine dioxygenase 2 (TET2) mutation. There are limited therapeutic options available for these diseases, and single agents have only modest efficacy. In this phase 2 study, the authors combined multiple active agents (thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid [TADA]) to treat patients with these disorders.
  
  
  METHODS
  This multicenter trial was conducted from January 2005 to July 2007. The primary endpoint was to evaluate the efficacy of TADA therapy. Patients received the combination for one 12-week cycle followed by maintenance thalidomide for an additional 3 months. Response was assessed using International Working Group criteria.
  
  
  RESULTS
  Among 28 enrolled patients, the median age was 66.5 years; 15 patients had MDS/MPN-unclassifiable, 8 patients had chronic myelomonocytic leukemia type 1, and 5 patients had PMF. Approximately 60% of the patients had normal cytogenetics. The JAK2V617F mutation was detected in 5 of 14 tested patients, and TET2 mutations were detected in 2 of 8 tested patients. Almost half of the patients had splenomegaly. With a median on-study follow-up of 5.7 months, 21 patients (75%) completed the entire 12-week course of therapy, and 6 patients (29%) responded to TADA. With a median extended follow-up of 24.1 months for 15 evaluable patients, the median progression-free survival was 14.4 months, and the median overall survival was 21.4 months.
  
  
  CONCLUSIONS
  The TADA regimen yielded clinical responses in patients with PMF and MDS/MPN. To the authors' knowledge, this study represents the first trial targeting this patient population. The results indicated that it is reasonable to incorporate multiple novel agents in the treatment of these rare diseases.
authors.affiliation: Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
authors.forename: Nelli
authors.initials: N
authors.lastname: Bejanyan
authors.forename: Ramon V
authors.initials: RV
authors.lastname: Tiu
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.forename: Ania
authors.initials: A
authors.lastname: Jankowska
authors.forename: Matt
authors.initials: M
authors.lastname: Kalaycio
authors.forename: Anjali
authors.initials: A
authors.lastname: Advani
authors.forename: Josephine
authors.initials: J
authors.lastname: Chan
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.forename: Lindsey
authors.initials: L
authors.lastname: Mooney
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D001205:Ascorbic Acid / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D054437:Myelodysplastic-Myeloproliferative Diseases / Q000188:drug therapy*; D010087:Oxides / Q000008:administration & dosage; D055728:Primary Myelofibrosis / Q000188:drug therapy*; D013792:Thalidomide / Q000008:administration & dosage
chemical_list: D001152:Arsenicals; D010087:Oxides; D013792:Thalidomide; D003907:Dexamethasone; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide