Correspondence
Eculizumab in Paroxysmal Nocturnal Hemoglobinuria
N Engl J Med 2006; 355:2786-2788December 28, 2006
- Article
To the Editor:
The study of eculizumab by Hillmen et al. (Sept. 21 issue)1 showed stabilization of hemoglobin levels and a reduction in transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria (PNH). However, there were more patients with a history of aplastic anemia in the placebo group than in the eculizumab group (27% vs. 14%), and the median duration of PNH was longer in the placebo group (9.2 years vs. 4.3 years). These differences may have favored the eculizumab group.
Moreover, the more frequent use of anticoagulant agents in the eculizumab group (in 49% of patients, vs. 25% of those in the placebo group) might have prevented thrombosis in patients in the eculizumab group, apart from possible terminal complement inhibition. By the 26th week, about half the patients in the eculizumab group required blood transfusions despite continued use of the drug.
1 ReferencesSatheesh K. Kathula, M.D.
Wright State University, Dayton, OH 45409
kathulask@yahoo.com 1
Hillmen P ,Young NS ,Schubert J , et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233-1243
Full Text | Web of Science | Medline
To the Editor:
In the study by Hillmen et al., it is not clear whether the patients were randomly assigned to study groups according to the level of expression of glycosylphosphatidylinositol (GPI) anchors on granulocytes. Unlike red cells that are deficient in GPI anchors, PNH granulocytes have a normal life span.1,2 Therefore, the proportion of abnormal granulocytes more accurately reflects the size of the PNH clone and is unaffected by red-cell transfusion.1,2
Information on the ethnic background of patients in this study would be interesting, since the natural history of PNH in Americans and Europeans appears to differ from that in Asians, Pacific Islanders, and Hispanics.3 In addition, it would be good to know whether any patients in either group were pregnant, since women with PNH have a risk of serious complications or death during pregnancy, and whether eculizumab is safe to use in this high-risk group.4
4 ReferencesJaswinder Singh, M.D.
Kansas University Medical Center, Kansas City, KS 66160-7353Ashok K. Malani, M.D., F.R.C.S.
Maninder Pabla, M.D.
Heartland Regional Medical Center, St. Joseph, MO 64507
drmalani@yahoo.com 1
Rosse WF . The life-span of complement-sensitive and -insensitive red cells in paroxysmal nocturnal hemoglobinuria. Blood 1971;37:556-562
Web of Science | Medline2
Brubaker LH ,Essig LJ ,Mengel CE . Neutrophil life span in paroxysmal nocturnal hemoglobinuria. Blood 1977;50:657-662
Web of Science | Medline3
Araten DJ ,Thaler HT ,Luzzatto L . High incidence of thrombosis in African-American and Latin-American patients with paroxysmal nocturnal haemoglobinuria. Thromb Haemost 2005;93:88-91
Web of Science | Medline4
Tichelli A ,Socie G ,Marsh J , et al. Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression. Ann Intern Med 2002;137:164-172
Web of Science | Medline
To the Editor:
In the study by Hillmen et al., PNH clones were expanded during the administration of eculizumab. PNH clones occur in myelodysplastic syndromes and acute leukemia.1,2 Genetic instability might be a component of PNH.3 Given these findings, there is concern about the risk of secondary hematologic cancers in patients with PNH during long-term administration of eculizumab.
3 ReferencesMorihito Takita, M.D.
Tomoko Matsumura, M.D.
Masahiro Kami, M.D.
University of Tokyo, Tokyo 108-8639, Japan1
Socie G ,Mary JY ,de Gramont A , et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. Lancet 1996;348:573-577
CrossRef | Web of Science | Medline2
Meletis J ,Terpos E . Recent insights into the pathophysiology of paroxysmal nocturnal hemoglobinuria. Med Sci Monit 2003;9:RA161-RA172
Medline3
Horikawa K ,Kawaguchi T ,Ishihara S , et al. Frequent detection of T cells with mutations of the hypoxanthine-guanine phosphoribosyl transferase gene in patients with paroxysmal nocturnal hemoglobinuria. Blood 2002;99:24-29
CrossRef | Web of Science | Medline
To the Editor:
Hillmen et al. report a statistically significant difference in almost all measures on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Perhaps it would have been more appropriate to compare quality-of-life measures in the eculizumab group with those in historical controls who were not receiving placebo infusions either weekly or every 2 weeks.
Yuri B. Pride, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
ypride@bidmc.harvard. edu Author/Editor Response
With regard to the comments by Kathula, it is notable that all patients with PNH have an underlying aplastic process, regardless of their history.1 There were no differences in cytopenia in the groups we studied, indicating similar marrow function in the two groups. Neither the duration of PNH nor a history of aplasia would have affected the outcome of the trial. The difference in the use of anticoagulant agents in this randomized study was due to chance. Thrombosis was not an end point, and we did not speculate with regard to the one thrombotic event that occurred in the placebo group. More than half the patients did not need transfusions, and the remaining patients had a 44% reduction in transfusion requirements. All eculizumab-treated patients had a dramatic reduction in intravascular hemolysis, which led to clinically significant improvements in fatigue and the quality of life.
I agree with Singh et al. that the proportion of PNH granulocytes accurately reflects the clone size. There was no difference in the proportion of GPI-deficient granulocytes between the eculizumab group and the placebo group at baseline (median, 81.0% and 82.7%, respectively). Most patients in the study (86.0% in the eculizumab group and 93.2% in the placebo group) were white, and no conclusions can be drawn regarding the use of eculizumab in various ethnic groups. Pregnancy was an exclusion criterion, and all women of childbearing potential had a negative pregnancy test before enrollment. A single patient who became pregnant while receiving eculizumab discontinued treatment in accordance with the protocol and had a successful full-term birth without complications.
With regard to the comments of Takita et al., it is true that eculizumab caused an increase in the proportion of PNH erythrocytes by preventing the complement-mediated destruction of these cells. However, the proportion of PNH granulocytes remained constant in patients receiving eculizumab in this study and in a previous phase 2 study,2,3 in which patients received eculizumab for more than 4 years. Eculizumab had no direct effect on the PNH clone and would not be expected to alter the risk of secondary hematologic cancers. No new cases of the myelodysplastic syndrome or hematologic cancers have occurred in patients with PNH who received eculizumab.
The question by Pride concerning our use of placebo to assess the quality of life of patients is curious. We consider the inclusion of the placebo group in the double-blind study as a strength, not a weakness, since both the eculizumab group and the placebo group received matched therapeutic interventions, which served to reduce bias. In previous reports on eculizumab in a small group of patients with PNH,2,3 similar improvements in quality of life were demonstrated, as compared with the same patients before treatment.
3 ReferencesPeter Hillmen, M.B., Ch.B., Ph.D.
Leeds General Infirmary, Leeds LS1 3EX, United Kingdom
peter.hillmen@nhs. net 1
Rotoli B ,Luzzatto L . Paroxysmal nocturnal haemoglobinuria. Baillieres Clin Haematol 1989;2:113-138
CrossRef | Medline2
Hillmen P ,Hall C ,Marsh JC , et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:552-559
Full Text | Web of Science | Medline3
Hill A ,Hillmen P ,Richards SJ , et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 2005;106:2559-2565
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Alexander F. Scheuerle, Nermin Serbecic, Sven C. Beutelspacher. (2009) Paroxysmal nocturnal hemoglobinuria may cause retinal vascular occlusions. International Ophthalmology 29:3, 187-190
CrossRef
