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Not only does the experimental drug AMG 531 appear to be safe in thrombocytopenic patients with myelodysplastic syndrome, but it also shows signs of prompting a clinically meaningful response, Dr. Hagop Kantarjian reported in a poster.
Overall, 45% of patients achieved a platelet response in the open-label, sequential dose-escalation study. This included 32% who had a complete platelet response, and 13% who had a major platelet response. Complete response was defined as achieving a peak platelet count of at least 100 x 109/L during treatment. Major response was defined as an increase in platelet count of at least 30 x 109/L. Patients who received platelet transfusions during the treatment period were considered nonresponders (Blood 2000;96:3671-4).
AMG 531 also decreased platelet transfusions for responders compared with nonresponders (3 events vs. 91), based on data presented by Dr. Kantarjian, chair of the department of leukemia at the University of Texas M.D. Anderson Cancer Center, Houston.
AMG 531 is a thrombopoiesis-stimulating Fc-peptide fusion protein. AMG 531 binds to thrombopoietin receptor c-Mpl, a member of the hematopoietic growth factor receptor superfamily.
Dr. Kantarjian disclosed no conflicts of interest. Several of his collaborators are employees of Amgen Inc., which is developing the experimental agent.
Subjects had a low or intermediate risk of primary myelodysplastic syndrome (MDS). They could not be receiving any other therapies for MDS except supportive care. Platelet count at entry had to be no greater than 50 x 109/L, based on a mean of two counts, with no count greater than 55 x 109/L.
All told, 44 patients received three weekly subcutaneous injections of AMG 531. The study tested four doses: 300 mcg (6 patients), 700 mcg (11), 1,000 mcg (11), and 1,500 mcg (16). After week 4, patients could continue in a treatment extension at their assigned doses or be escalated to a responding dose. All completed the original treatment, and most (91%) opted to continue.
Based on the 2000 criteria, 32% had a complete response: two patients in the 300-mcg group, three in the 700-mcg group, three in the 1,000-mcg group, and six in the 1,500-mcg group. Another 14% had major platelet responses: one in the 300-mcg group, two in the 700-mcg group, one in the 1,000-mcg group, and two in the 1,500-mcg group.
In an ad hoc analysis using platelet response criteria from 2006, 52% of patients achieved platelet response defined as an absolute increase of at least 30 x 109/L with a baseline count of more than 20 x 109/L. A patient could also have a platelet response with a baseline count of up to 20 x 109/L, if the count increased to more than 20 x 109/L and by at least 100% without platelet transfusions within 72 hours of the platelet count. Using the same criteria, durable platelet response—defined as lasting for 4 consecutive weeks beyond the treatment period—was achieved in 32% of patients.
In terms of median change in platelet count from baseline, patients in the 700-mcg group had the most impressive responses from week 2 through week 4 (a roughly 50% increase from baseline). "What's interesting here is that there actually was maximal benefit at an intermediate dose (700 mcg). ... [When] you went up from there, you actually lost benefit, suggesting again that the maximal tolerated dose isn't always the optimal dose," Dr. Ross Levine of Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, commented during a discussion session.
Kantarjian H.M. et al. Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study. Abstract 7032.
Commentary |
Myelodysplastic syndrome is an increasingly frequent diagnosis, especially in elderly individuals who present with some degree of anemia. Some patients are transfusion dependent, others are asymptomatic, and many are at high risk of developing acute myeloid leukemia. Supportive therapies including erythropoietic-stimulating agents, blood transfusions, and granulocyte colony-stimulating factor have been available for many years to clinicians caring for these patients, but platelet-specific agents remain elusive. More recently, the hypomethylating agents azacytidine and decitabine have been approved for all stages of the disease. These epigenetic regulators can both improve peripheral blood cytopenias and clear bone marrow blasts. Two studies raise the possibility of new therapeutic agents for myelodysplastic syndrome. In the first, Amgen's AMG-31 was given to lower-risk MDS patients with thrombocytopenia. This thrombopoiesis-stimulating agent previously showed benefit in trials of patients with idiopathic thrombocytopenia purpura. In the most recent MDS study, almost half of the treated patients achieved a complete or major platelet response. Expanded studies using the optimal dose defined in this trial should provide further safety and efficacy information. The second study combined azacytidine with the histone-deacetylase (HDAC) inhibitor MGCD0101 in advanced MDS as well as in acute myelogenous leukemia patients. HDAC inhibitors have shown synergistic antitumor activity with hypomethylating agents in laboratory studies. The complete and partial responses observed justify ongoing trials of this intriguing combination. — Steven E. Coutré, M.D.
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