PURPOSE: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose. EXPERIMENTAL DESIGN: Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies. RESULTS: A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence. CONCLUSIONS: Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
PURPOSE: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose. EXPERIMENTAL DESIGN: Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies. RESULTS: A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence. CONCLUSIONS:Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
Authors: Jimmy J Hwang; John Kuruvilla; David Mendelson; Michael J Pishvaian; J F Deeken; Lillian L Siu; Mark S Berger; Jean Viallet; John L Marshall Journal: Clin Cancer Res Date: 2010-06-10 Impact factor: 12.531
Authors: Elizabeth A Brem; Karen Thudium; Sapna Khubchandani; Ping-Chiao Tsai; Scott H Olejniczak; Seema Bhat; Wasif Riaz; Jenny Gu; Arshad Iqbal; Ryan Campagna; Joy Knight; Cory Mavis; Paul Hoskin; George Deeb; John F Gibbs; Gerald Fetterly; Myron S Czuczman; Francisco J Hernandez-Ilizaliturri Journal: Br J Haematol Date: 2011-04-15 Impact factor: 6.998
Authors: Alyse N Douglass; Heather S Kain; Marian Abdullahi; Nadia Arang; Laura S Austin; Sebastian A Mikolajczak; Zachary P Billman; Jen C C Hume; Sean C Murphy; Stefan H I Kappe; Alexis Kaushansky Journal: Mol Ther Date: 2015-02-04 Impact factor: 11.454