Subject(s)
Cyclopentanes/adverse effects , Enzyme Inhibitors/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Pyrimidines/adverse effects , Adult , Aged , Aged, 80 and over , Cyclopentanes/administration & dosage , Enzyme Inhibitors/administration & dosage , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , NEDD8 Protein/antagonists & inhibitors , Pyrimidines/administration & dosage , Young AdultABSTRACT
The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F- or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.
Subject(s)
Myeloproliferative Disorders/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Animals , Apoptosis/drug effects , Bone Marrow/metabolism , Bone Marrow/pathology , Cell Cycle Checkpoints/drug effects , Cell Line , Cell Proliferation/drug effects , Disease Models, Animal , Female , Fusion Proteins, bcr-abl/deficiency , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/genetics , Liver/metabolism , Liver/pathology , Megakaryocytes/drug effects , Megakaryocytes/metabolism , Mice , Mutation , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/pathology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation/drug effects , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Spleen/drug effects , Spleen/metabolismABSTRACT
Eg5 (kinesin spindle protein) is a microtubule motor protein, essential for centrosome separation during mitosis. This Phase I/II, open-label, multicenter, two-part study investigated AZD4877, a potent Eg5 inhibitor, in patients with acute myeloid leukemia. Primary objectives were to determine the maximum tolerated dose (MTD) (part A), assess efficacy (part B) and determine the pharmacokinetic profile (parts A and B). Secondary objectives included assessment of safety and tolerability. AZD4877 was administered at a range of doses (2, 4, 7, 10, 13, 16 and 18 mg/day) as a 1-hour intravenous infusion on three consecutive days of a continuous 2-week schedule. The MTD in part A was defined as 16 mg/day based on dose-limiting stomatitis at 16 and 18 mg/day, hyperbilirubinemia at 16 mg/day and palmar-plantar erythrodysesthesia syndrome at 18 mg/day. Systemic exposure to AZD4877 generally increased with increasing dose whereas half-life was not dose dependent. No evaluable patients experienced a complete remission (CR) or CR with incomplete blood count recovery (CRi), demonstrating no evidence of AZD4877 efficacy in this population. Evidence of monoasters in all but the 4 mg/day dose group provided proof of mechanism for AZD4877. This study was terminated due to lack of efficacy. (ClinicalTrials.gov identifier NCT00486265).
Subject(s)
Antimitotic Agents/administration & dosage , Benzamides/administration & dosage , Kinesins/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Pyrimidinones/administration & dosage , Adult , Aged , Aged, 80 and over , Antimitotic Agents/adverse effects , Antimitotic Agents/pharmacokinetics , Benzamides/adverse effects , Benzamides/pharmacokinetics , Female , Humans , Leukemia, Myeloid, Acute/blood , Male , Middle Aged , Pyrimidinones/adverse effects , Pyrimidinones/pharmacokinetics , Young AdultABSTRACT
BACKGROUND: The standard approach to treatment of relapsed/refractory Hodgkin's lymphoma (HL) is high-dose chemotherapy conditioning followed by autologous hematopoietic stem-cell transplantation (aHSCT). We report the results of a prospective phase I/II clinical trial of accelerated hyperfractionated total lymphoid irradiation (TLI) immediately followed by high-dose chemotherapy for relapsed/refractory HL. PATIENTS AND METHODS: Forty-eight patients underwent aHSCT with either sequential TLI/chemotherapy (n = 32) or chemotherapy-alone conditioning (n = 16), based on prior radiation exposure. The first 22 patients enrolled on trial received escalating doses of etoposide (1600-2100 mg/m(2)) with high-dose carboplatin and cyclophosphamide. RESULTS: No dose-limiting toxicity was seen and TLI/chemotherapy was well tolerated. The 5-year event-free survival (EFS) estimate for all patients was 44% with overall survival (OS) of 48%. Five-year EFS and OS for the TLI/chemotherapy group was 63% and 61%, respectively, compared with 6% and 27%, respectively, for the chemotherapy-alone group (P < 0.0001 and P = 0.04, respectively). Patients with primary induction failure HL who received TLI/chemotherapy had 5-year EFS and OS rate of 83%. The 100-day treatment-related mortality was 4.2% and two secondary cancers were seen. Significant factors predicting survival by multivariate analysis included TLI/chemotherapy conditioning and B symptoms at relapse. CONCLUSIONS: Sequential TLI/chemotherapy conditioning for relapsed/refractory HL is safe and associated with excellent long-term survival rates.