Correspondence

AMG 531 for Chronic ITP

N Engl J Med 2007; 356:307-308January 18, 2007

Article

To the Editor:

Bussel et al. (Oct. 19 issue)1 justify the rationale for using the thrombopoiesis-stimulating drug AMG 531 in chronic immune thrombocytopenic purpura (ITP) by citing previous reports on abnormalities of megakaryocytic survival and maturation in this disorder. However, studies of defective platelet production in ITP have yielded conflicting results,2,3 and the present study provides no evidence of such an abnormality in any patient. Furthermore, there is no information on changes in megakaryocytic mass or serum thrombopoietin levels after treatment with AMG 531, and it is unclear whether this drug truly abrogates abnormalities of platelet production. In addition, the recruitment of ineligible patients (one patient received rituximab 4 weeks before enrollment, thereby violating entry criteria), differences in corticosteroid dosages in the phase 1 study, inappropriate dosing, and the failure to relate toxicity data to the platelet count make this study scientifically and clinically weak.

Sudhir Tauro, Ph.D., M.R.C.P.
University of Dundee, Dundee DD1 9SY, United Kingdom
s.tauro@dundee.ac.uk

3 References

1. 1

   Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006;355:1672-1681[Erratum, N Engl J Med 2006;355:2054.]
   Full Text | Web of Science | Medline

2. 2

   Hoffman R, Mazur E, Bruno E, Floyd V. Assay of an activity in the serum of patients with disorders of thrombopoiesis that stimulates formation of megakaryocytic colonies. N Engl J Med 1981;305:533-538
   Full Text | Web of Science | Medline

3. 3

   Bellucci S, Han ZC, Caen JP. Studies of in vitro megakaryocytopoiesis in adult immune thrombocytopenic purpura (ITP). Eur J Haematol 1991;47:86-90
   CrossRef | Web of Science | Medline

To the Editor:

In their study of AMG 531 in patients with chronic ITP, Bussel et al. state that 29% of patients in phase 1 and 33% of patients in phase 2 of the study were receiving corticosteroids. However, on the basis of the data presented, it is not possible to tell which patients were receiving corticosteroids and whether corticosteroids may have potentiated the effects of AMG 531. It would be useful to know whether there were differences in the response to and the required dose of AMG 531 between the patients who were receiving corticosteroids and those who were not receiving them. Since corticosteroids are still the mainstay of therapy in many patients, it may be useful to know whether there is any synergy between corticosteroids and AMG 531.

Keshava Prasad, M.D., M.R.C.P.
University of Arkansas for Medical Sciences, Little Rock, AR 72205
hskprasad@pol.net

Author/Editor Response

Tauro raises a number of points regarding the treatment of ITP with AMG 531. It was not the goal of our study to show impaired megakaryopoiesis in patients with ITP. The references cited by Tauro deal with in vitro studies of megakaryocytopoiesis in patients with this condition, and the results of these studies are inconsistent. Although our study did not include any platelet kinetic studies to prove this mechanism, the activity of Mpl ligands is limited in scope; the primary effect of these ligands is to increase platelet production.

With regard to ineligible patients, all patients were eligible at the time of enrollment. During the study, the protocol was amended to avoid confounding results from rituximab treatment by increasing the time since the administration of the last dose from 4 weeks to 16 weeks. In addition, Tauro comments that some patients received “inappropriate dosing.” All patients received doses according to the study protocol; some probably received suboptimal doses as an unavoidable outcome of the dose-finding study. Also, in phase 1, there were indeed small differences in concomitant corticosteroid use between the groups of patients who received 0.2 to 1 μg of AMG 531 per kilogram of body weight and those who received 3 to 10 μg per kilogram, but the analysis did not show a relationship between platelet response and corticosteroid use. Finally, with regard to the absence of a relationship between toxicity and the platelet count, we show in Table 2 of our report that the only dose-related toxicity associated with AMG 531 was headache; all bleeding-related toxicity was clearly related to the thrombocytopenia that occurred in patients who received placebo or that occurred after the discontinuation of treatment with AMG 531.

We agree with Prasad that the potential for additive effects of or synergy between corticosteroids and AMG 531 is important to explore. In our study, patients received stable doses of corticosteroids, so we could not test for synergy; the response rate and the extent of the response were not related to corticosteroid use. In a subsequent study, AMG 531 appeared to be corticosteroid sparing and to be potentiated by corticosteroids.

James B. Bussel, M.D.
Weill Medical College of Cornell University, New York, NY 10021
jbussel@med.cornell.edu

David J. Kuter, M.D., D.Phil.
Massachusetts General Hospital, Boston, MA 02114

Janet L. Nichol, M.S.
Amgen, Thousand Oaks, CA 91320-1799

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1. 1

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