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.
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: Michael R Savona; Luca Malcovati; Rami Komrokji; Ramon V Tiu; Tariq I Mughal; Attilio Orazi; Jean-Jacques Kiladjian; Eric Padron; Eric Solary; Raoul Tibes; Raphael Itzykson; Mario Cazzola; Ruben Mesa; Jaroslaw Maciejewski; Pierre Fenaux; Guillermo Garcia-Manero; Aaron Gerds; Guillermo Sanz; Charlotte M Niemeyer; Francisco Cervantes; Ulrich Germing; Nicholas C P Cross; Alan F List Journal: Blood Date: 2015-01-26 Impact factor: 22.113
Authors: Eric Padron; Amy Dezern; Marcio Andrade-Campos; Kris Vaddi; Peggy Scherle; Qing Zhang; Yan Ma; Maria E Balasis; Sara Tinsley; Hanadi Ramadan; Cassandra Zimmerman; David P Steensma; Gail J Roboz; Jeffrey E Lancet; Alan F List; Mikkael A Sekeres; Rami S Komrokji Journal: Clin Cancer Res Date: 2016-02-08 Impact factor: 12.531
Authors: Minmin Liu; Hitoshi Ohtani; Wanding Zhou; Andreas Due Ørskov; Jessica Charlet; Yang W Zhang; Hui Shen; Stephen B Baylin; Gangning Liang; Kirsten Grønbæk; Peter A Jones Journal: Proc Natl Acad Sci U S A Date: 2016-08-29 Impact factor: 11.205
Authors: Tariq I Mughal; Nicholas C P Cross; Eric Padron; Ramon V Tiu; Michael Savona; Luca Malcovati; Raoul Tibes; Rami S Komrokji; Jean-Jacques Kiladjian; Guillermo Garcia-Manero; Attilio Orazi; Ruben Mesa; Jaroslaw P Maciejewski; Pierre Fenaux; Raphael Itzykson; Ghulam Mufti; Eric Solary; Alan F List Journal: Haematologica Date: 2015-09 Impact factor: 9.941