Hill A

Hillmen P.

Kelly R

Luzzatto L

Notaro R

RISITANO, ANTONIO MARIA

Archivio della ricerca - Università degli studi di Napoli Federico II

T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 363;23 nejm.org december 2, 20102270line and were thus excluded as not being clearly premenopausal. After the inclusion of women who had at least 1 year of follow-up and for whom menstrual-history data were sufficient at 12 months, the final study populations included 1885 women for overall survival and 1837 for disease-free survival. Among women with amenorrhea, there was significant improvement in overall sur-vival (hazard ratio for death, 0.72; P = 0.04) and in disease-free survival (hazard ratio for disease recurrence, a second malignant condition, or death, 0.65; P<0.001) (Fig. 1A and 1B). We also performed a 12-month landmark analysis for subgroups of patients on the basis of their estrogen-receptor (ER) status. Women with ER-positive tumors who had amenorrhea had a significantly better outcome than those who did not have amenorrhea, with a hazard ratio for death of 0.52 (P = 0.002) and a hazard ratio for disease recurrence, a second malignant condition, or death of 0.51 (P<0.001). By con-trast, women with ER-negative tumors had a similar outcome regardless of whether they had amenorrhea, with a hazard ratio for death of 1.08 (P = 0.76) and a hazard ratio for disease recurrence, a second malignant condition, or death of 0.96 (P = 0.85).In the landmark analysis, the percent differ-ences in drug doses between women with amen-orrhea and those without amenorrhea were small (Fig. 1C). When the differences were evaluated according to tumor ER status, study group, and specific drug, there was only one instance in which the relative difference was more than 3.8%. (In this instance, there was a relative increase of 9.7% in the dose of docetaxel received as part of sequential chemotherapy by women with ER-posi-tive tumors who had amenorrhea.)Thus, premenopausal women in whom amen-orrhea developed as a consequence of adjuvant therapy had significantly better overall survival and disease-free survival than did women with-out amenorrhea, particularly when the tumor was ER-positive. Furthermore, the dose of the che-motherapy drug that was delivered was not a key factor in explaining the differences.Sandra M. Swain, M.D.Washington Hospital Center Washington, DC sandra.m.swain@medstar.netJong-Hyeon Jeong, Ph.D.University of Pittsburgh Pittsburgh, PANorman Wolmark, M.D.Allegheny General Hospital Pittsburgh, PADisclosure forms provided by the authors are available with the full text of this letter at NEJM.org.1.	 Swain SM, Jeong J-H, Geyer CE Jr, et al. Longer therapy, iat-rogenic amenorrhea, and survival in early breast cancer. N Engl J Med 2010;362:2053-65.Paroxysmal	Nocturnal	Hemoglobinuria	— Hemolysis	before	and	after	EculizumabTo the Editor: The letter to the Editor by Ber-zuini et al. (Sept. 2 issue)1 shows in a single ex-ample that in patients with paroxysmal nocturnal hemoglobinuria (PNH) who are receiving eculiz-umab, intravascular hemolysis is abrogated, but extravascular hemolysis becomes apparent, con-sequent to C3 binding to red cells, specifically to the red cells with the PNH phenotype, since they lack CD55. Two series involving 41 patients2 and 31 patients3 had already shown that this interest-ing phenomenon has been observed regularly in patients with PNH who are receiving eculizumab. Decreased red-cell survival measured in vivo2 provided definitive proof of a hemolytic process.However, from the letter to the Editor by Ber-zuini and colleagues, readers may get the im-pression that C3 binding on PNH red cells is au-tomatically a major clinical problem and that prednisone is the answer.  We are concerned about such an impression for three reasons. First, in most patients, this phenomenon has relatively little clinical relevance. For instance, an adequate level of hemoglobin may be maintained in a patient even when up to 80% of the PNH red cells have bound C3 (Fig. 1). Second, patients with PNH are facing a long course: in the past, many of them have had a variety of serious side effects of long-term use of glucocorticoids (such as “moon face” appearance, diabetes, hip necrosis, and even severe infection), despite the lack of evidence that the use of these agents was of any benefit.4 Third, in the patient reported on by Berzuini et correspondencen engl j med 363;23 nejm.org december 2, 2010 2271al., the follow-up is far too short to prove that prednisone is beneficial. If prednisone is to be used to control extravascular hemolysis in pa-tients with PNH who are receiving eculizumab, this should be done in the context of a clinical trial. Our experience with 14 patients suggests that this approach is not effective. In one patient, splenectomy was successful,5 but this operation is not free of risk (in terms of thrombosis and otherwise), and it cannot be recommended as a routine approach.Fortunately, even the minority of patients who, in terms of hemoglobin level, have only a limited response to eculizumab usually have improve-ment in symptoms such as abdominal pain and dysphagia, and the risk of thrombosis is proba-bly decreased considerably among them, regard-less of their extravascular hemolysis. Eventually, C3-mediated extravascular hemolysis might be overcome by a new intervention appropriately tar-geting C3. In the meantime, the last thing one would want is to have these patients burdened by the side effects associated with the long-term use of glucocorticoids (including a higher risk of infection), in addition to their infusions of ecu-lizumab every 2 weeks.Hemoglobin (g/liter), GPI-Negative Red Cells (%), and C3+ Red Cells (%)140100120100101102103104806040200Reticulocytes (×10−9/liter) and LDH (U/liter)5000800400060010004002000BeforeTreatment0 3 6 9 12 15100 101 102 103 10418 21 24 27Months since Initiation of EculizumabReticulocytesLDHHemoglobinGPI-negative red cellsC3+ red cellsC3d–FITCCD59–PE9.5%76.2%14.3%Figure	1.	Clinical	Course	of	a	50-Year-Old	Patient	with	Severe	Hemolytic	Paroxysmal	Nocturnal	Hemoglobinuria.	From the time of diagnosis in 2004, the patient required an average of 3 units of packed red cells per month until May 2008, when she began to receive eculizumab treatment. After approximately 2 years, apart from normalization of the lactate dehydrogenase (LDH) level, there was an increase in glycosylphosphatidylinositol (GPI)−negative red cells; concomitantly, the steady-state hemoglobin level was approximately 12 g per deciliter, despite the fact that 76% of red cells (or 84% of PNH red cells) had bound C3d (see the inset, which shows the results of the flow cyto-metric analysis of the C3d deposition on a proportion of CD59 cells from the same patient). The reticulocyte count remained elevated, indicating continued extravascular hemolysis. The patient did not receive glucocorticoids.  FITC denotes fluorescein isothiocyanate, and PE phycoerythrin.T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 363;23 nejm.org december 2, 20102272Antonio M. Risitano, M.D., Ph.D.Federico II University  Naples, ItalyRosario Notaro, M.D. Lucio Luzzatto, M.D.Istituto Toscano Tumori  Florence, Italy lucio.luzzatto@ittumori.itAnita Hill, M.B., Ch.B., Ph.D. Richard Kelly, M.B., Ch.B. Peter Hillmen, M.B., Ch.B., Ph.D.St. James’s University Hospital  Leeds, United KingdomDisclosure forms provided by the authors are available with the full text of this letter at NEJM.org.1.	 Berzuini A, Montanelli F, Prati D. Hemolytic anemia after eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2010;363:993-4.2.	 Risitano AM, Notaro R, Marando L, et al. Complement frac-tion 3 binding on erythrocytes as additional mechanism of dis-ease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 2009;113:4094-100.3.	 Hill A, Rother RP, Arnold L, et al. Eculizumab prevents in-travascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010;95: 567-73.4.	 Parker C, Omine M, Richards S, et al. Diagnosis and man-agement of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106:3699-709.5.	 Risitano AM, Marando L, Seneca E, Rotoli B. Hemoglobin normalization after splenectomy in a paroxysmal nocturnal hemoglobinuria patient treated by eculizumab. Blood 2008;112: 449-51.Correspondence Copyright © 2010 Massachusetts Medical Society.instructions for letters to the editorLetters	to	the	Editor	are	considered	for	publication,	subject	to	 editing	 and	 abridgment,	 provided	 they	 do	 not	 contain	material	 that	 has	 been	 submitted	 or	 published	 elsewhere.	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In the first paragraph of the Treatment Goals subsection of Discussion of Management (page 1065), the fourth sentence should have read “Two — azacitidine and decitabine — are hypomethylating agents, which are thought to reactivate genes silenced due to hypermethylation in myeloid precursors,” rather than “. . . agents, which inactivate genes associated with proliferation and survival in myeloid pre-cursors.” The article has been corrected at NEJM.org.Performance of Common Genetic Variants in Breast-Cancer Risk Models (March 18, 2010;362:986-93). In Table 3 (page 990), the chromosome listed for the RS3803662 SNP should have been 16q, rather than 10q, and the chromosome listed for RS889312 should have been 5q, rather than 16q. The article has been corrected at NEJM.org.Mortality Attributable to Smoking in China (January 8, 2009; 360:150-9). In the sixth paragraph of the Discussion section, beginning “Ezzati and Lopez estimated . . .” (page 156), the parenthetical information should have been given in thou-sands, rather than millions. The article has been corrected at NEJM.org.noticesNotices submitted for publication should contain a mailing address and telephone number of a contact person or depart-ment. We regret that we are unable to publish all notices  received. Notices also appear on the Journal’s Web site (NEJM.org/medical-conference). 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Paroxysmal nocturnal hemoglobinuria--hemolysis before and after eculizumab.

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