Case Report Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome: A Report of 10 Cases Gianluigi Ardissino, MD, PhD, Sara Testa, MD, Ilaria Possenti, MD, Francesca Tel, MD, Fabio Paglialonga, MD, Stefania Salardi, BS, Silvana Tedeschi, MD, Mirco Belingheri, MD, and Massimo Cugno, MD Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and as many as 70% of patients with aHUS have mutations in the genes encoding complement regulatory proteins. Eculizumab, a humanized recombinant monoclonal antibody targeting C5, has been used successfully in patients with aHUS since 2009. The standard maintenance treatment requires life-long eculizumab therapy, but the possibility of discontinuation has not yet been tested systematically. We report the safety of discontinuing eculizumab treatment in 10 patients who stopped treatment with the aim of minimizing the risk of adverse reactions, reducing the risk of meningitis, and improving quality of life while also reducing the considerable treatment costs. Disease activity was monitored closely at home by means of urine dipstick testing for hemoglobin. During the cumulative observation period of 95 months, 3 of the 10 patients experienced relapse within 6 weeks of discontinuation, but then immediately resumed treatment and completely recovered. Our experience supports the possibility of discontinuing eculizumab therapy with strict home monitoring for early signs of relapse in patients with aHUS who achieve stable remission. Am J Kidney Dis. -(-):---. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Atypical hemolytic uremic syndrome; eculizumab; discontinuation.
A
typical hemolytic-uremic syndrome (aHUS) is a rare, life-threatening, chronic thrombotic microangiopathy (TMA) that often is due to uncontrolled complement dysregulation1-3; it accounts for 10%-15% of all HUS cases in children, but also affects adults.4-6 Approximately 60%-70% of patients with aHUS have mutations in the genes encoding complement factor H (CFH), factor I (CFI), membrane cofactor protein (MCP), factor B (CFB), thrombomodulin (THBD), and C3.7-11 Anti-CFH antibodies also may contribute to the pathogenesis of the disease and often are associated with deletions in the CFH-related genes CFHR3 and CFHR1 (referred to as CFHR3/R1).12 For years, the only available treatment was plasma exchange, but outcomes were poor and up to 60% of patients with CFH mutations (the most severe form) reached end-stage renal disease shortly after onset.13,14 Since 2009, aHUS has been treated successfully with eculizumab, a monoclonal antibody targeting C5 and preventing complement activation. Eculizumab treatment is associated with an increased risk of meningococcal infection, and mandatory vaccination only reduces the risk.15 The drug was approved by the US Food and Drug Administration for use in aHUS treatment in September 2011, but the optimal treatment schedule has not yet been established.16 A number of publications indicate that long-term therapy is necessary to prevent relapses, and the European Medicines Agency has approved life-long treatment.2,3,17-21 We describe 10 patients with aHUS who discontinued eculizumab maintenance treatment after achieving disease remission. Am J Kidney Dis. 2014;-(-):---
CASE REPORTS Twenty-two patients with aHUS have started eculizumab treatment at our institution since 2010, all of whom were screened for complement dysregulation (CFH, CFI, CFB, MCP [encoded by the CD46 gene], C3, THBD gene mutations, and anti-CFH antibodies). After TMA had remitted or, if the drug was used to prevent recurrences, several weeks after kidney transplantation, patients were offered the choice of continuing or discontinuing eculizumab treatment. Clinical remission was defined as normal platelet count, normal lactate dehydrogenase and haptoglobin levels, no detectable schistocytes, and normal or stable kidney function assessed in terms of serum creatinine level and/or urinary protein excretion. The rationale for discontinuation was to reduce the risk of meningococcal infection, minimize the treatment’s impact on patients’ quality of life, prevent the development of immune-mediated drug reactions, and reduce the considerable treatment costs. The potential benefits of treatment discontinuation and the risk of relapses with severe possible consequences were explained carefully to patients and/or their parents. Patients and/or parents also were informed that discontinuation was not the standard of care and that the likelihood of relapse was high. The risk of acute transplant rejection triggered by aHUS relapse was discussed when applicable.
From the Center for HUS Prevention, Control and Management, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy. Received September 23, 2013. Accepted in revised form January 14, 2014. Address correspondence to Gianluigi Ardissino, MD, PhD, Center for HUS Control, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milano, Italy. E-mail:
[email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.01.434 1
2 Table 1. Patients’ Baseline Characteristics and Biomarkers of TMA Activity Before Eculizumab Discontinuation and at Last Available Observation
Patient No.
Age at aHUS Onset (y)
Sex
Complement Abnormalitya
Relapse
Time Since Start of Eculizumab (mo)
Duration of Eculizumab Discontinuation (mo)
Scr (eGFRb) T1
T2
Platelet Count (103/mL) T1
T2
LDH (IU/L) T1
T2
Haptoglobin (mg/dL) T1
T2
UPCR (mg/mg) T1
T2
1
4.3
M
CFH (p.Ser1191Leu)
Yes
31.0
1.5
0.92 (49)
0.80 (58)
334 290 367 206
97
103
0.67 0.17
2
37.7
F
CFH (p.Arg1210Cys) 1 CFI (p.Asp519Asn) 1 THBD (p.Ala43Thr)
Yes
25.2
0.9
1.41 (44)
1.25 (51)
244 227 482 219
117
94
1.53 0.96
3
52.7
M
CFI (p.Ile140Thr)
No
24.3
22.7
1.03 (97)
1.00 (100) 180 256 467 371
312
292
4
34.8
F
CFI (p.Gly269Ser)
No
21.5
10.1
2.72 (29)
2.54 (22)
281 286 406 403
98
88
1.38 0.70
5
2.6
M
CFI (p.Asp519Asn)
No
21.4
15.9
0.38 (132) 0.44 (117) 261 299 517 426
68
105
0.35 0.24
6
1.3
F
Homozygous deletion at CFHR3/R1 locus
No
19.9
6.5
0.29 (128) 0.27 (138) 447 390 688 654
91
60
3.46 2.32
7c
19.1
M
Anti-CFH antibody (titer, 27 IU)
No
19.8
14.2
1.33 (72)
245 167 390 325
236
178
0.14 0.08
8 9
5.4 13.3
F M
MCP (p.Phe175Val) Anti-CFH antibody (titer, 100 IU) 1 homozygous deletion at CFHR3/R1 locus
No No
14.0 11.2
13.5 8.6
1.28 (36) 0.52 (89) 300 420 682 423 0.64 (110) 0.58 (122) 268 298 435 371
46 108
78 106
3.21 0.20 0.22 0.19
10
10.9
F
CFH (p.Gln950His) 1 homozygous deletion at CFHR3/R1 locus 1 anti-CFH antibody (titer, 230 IU)
Yes
6.4
1.2
88
88
0.45 0.12
0.95 (73)
1.20 (79)
0.66 (105) 180 239 466 221
NA
0.08
Ardissino et al
Am J Kidney Dis. 2014;-(-):---
Abbreviations: aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H; CFHR3/R1, CFH-related genes CFHR3 and CFHR1; CFI, complement factor I; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); LDH, lactate dehydrogenase; MCP, membrane cofactor protein (encoded by the CD46 gene); NA, not available; Scr, serum creatinine (in mg/dL); T1, time of eculizumab discontinuation; T2, time of last follow up; THBD, thrombomodulin; UPCR, urinary protein-creatinine ratio. a Mutations in CFH, CFI, THBD, and MCP are given at the protein level using 3-letter amino acid codes, eg, p.Ser1191Leu is a substitution of the serine at amino acid 1191 by leucine. b GFR calculated using Schwartz formula in patients 18 years or younger and the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation in patients older than 18 years. c Eculizumab therapy was started as prevention of aHUS recurrence on kidney transplant.
Eculizumab Treatment Discontinuation in aHUS
Figure 1. Sequence of events during eculizumab treatment in a cohort of 10 patients with atypical hemolytic uremic syndrome who discontinued maintenance treatment. Serum creatinine (Scr) values (expressed in mg/dL) are shown at the time of stopping eculizumab therapy and the peak value at relapse (for patients who experienced relapse) and the last available value (for all patients). Arrows indicate relapse. Abbreviations: ab, antibody; CFH, complement factor H; CFHR3/R1, CFH-related genes CFHR3 and CFHR1; CFI, complement factor I; MCP, membrane cofactor protein; THBD, thrombomodulin.
Patients who chose to discontinue eculizumab maintenance treatment were monitored carefully using urine dipstick at home thrice weekly in order to detect disease reactivation early. In the event of detecting microscopic hematuria, patients were asked to return to the hospital immediately for further examination (including platelet count, hemoglobin, haptoglobin, lactate dehydrogenase, creatinine, and schistocyte levels, proteinuria, and microscopic hematuria) to diagnose or exclude TMA relapse. The study was approved by our institution’s Ethics Committee. Table 1 lists demographic and clinical characteristics of the 10 patients who discontinued eculizumab therapy at the time of discontinuation and end of the follow-up period. They all had dysregulated complement (genetic abnormalities and/or anti-CFH antibodies) and clearly had benefited from eculizumab therapy, having obtained clinical remission. Eight of the 10 patients had discontinued dialysis therapy, whereas the other 2 had never been dialyzed. Patients received eculizumab for a median of 5.6 (range, 0.4-14.2) months before its discontinuation. Figure 1 shows treatment management in each patient. Cumulative time off treatment was 95 (median, 9.3; range, 0.9-22.7) months. In 5 cases, hemoglobinuria was detected at home by means of hemoglobin-positive urine dipstick. Subsequent blood and urine tests showed no association with signs of TMA in 2 of these patients and hemoglobinuria spontaneously subsided. In the 3 other patients, relapse was confirmed and eculizumab therapy was resumed. The relapses occurred within 6 weeks (mean, 37 days) of the last eculizumab dose, and peak serum creatinine levels at the time of relapse ranged from 2.3-3.4 mg/dL. All 3 patients experienced rapid remission (only 1 required hospitalization) and recovered completely, with serum creatinine levels returning to prediscontinuation values. The other 7 patients remained in remission with no signs of acute disease.
DISCUSSION Our findings show that eculizumab maintenance treatment to prevent a relapse of aHUS can be discontinued and that discontinuation is relatively safe if specific measures to detect relapses early are systematically used. Discontinuing eculizumab therapy has been described previously in very limited experiences, with inconclusive results.22-26 The main rationale for discontinuing eculizumab therapy was to protect patients from the risk of the potentially devastating side Am J Kidney Dis. 2014;-(-):---
effects of meningococcal infection, to which patients with complement deficiencies are exposed because of diminished capacity for complement-mediated lysis of bacteria.27,28 The risk of meningococcal infection due to eculizumab-induced complement is anything but negligible (1 event per patient per 20 years of treatment), and it also is reasonable to think that the infection is more severe in patients treated with eculizumab. Eculizumab has become the frontline treatment for aHUS,7,29,30 and the standard schedule suggested for an adult patient includes an induction phase of 900 mg per week for 4 weeks, followed by 1,200 mg in week 5 and then 1,200 mg every 14 days as lifelong maintenance treatment.31 Eculizumab is highly effective; however, after aHUS is in stable remission, it may be difficult to motivate a patient to return to the hospital every other week of his or her life. Many of our patients were committed to discontinuing the drug therapy even though they had been informed that a relapse was very likely to occur eventually. After a patient has experienced a relapse, his or her commitment to regular drug infusions often becomes very strong. Paradoxically, the policy of discontinuation is made possible because of the efficacy of eculizumab itself, which means that a relapse is no longer the dramatic event it used to be when plasma exchange was the only therapy available. Another reason for avoiding life-long maintenance treatment is to prevent other adverse events, such as immune-mediated drug reactions, including the theoretical risk of developing neutralizing anti-drug antibodies that ultimately would deprive the patient of a life-saving therapeutic resource. Additionally, eculizumab is among the most expensive life-long medical treatments. At a price of $5,617 per vial, the annual cost of standard maintenance treatment ranges from $100,860 (for body weight , 10 kg) to $578,100 (for an adult).30,32 The total cost per year of 3
Ardissino et al
maintenance treatment for all 10 of our patients would have been more than $3.5 million, but our course led to a total saving of .$2.5 million. All 3 patients who experienced relapse after eculizumab therapy discontinuation had CFH-related aHUS; therefore, knowing whether this gene is mutated may help predict the likelihood of a relapse. Although relapses were severe, resuming eculizumab therapy was effective immediately in controlling the disease, and serum creatinine levels returned to prediscontinuation values. We preferred using home urine dipstick to detect relapses rather than sophisticated but poorly accessible laboratory tests that can be performed only occasionally. The urine dipstick’s sensitivity and specificity cannot be calculated based on our limited data set, but all patients who experienced relapse were identified promptly (suggesting high sensitivity) and there were only 2 false-positive results (suggesting low specificity). In conclusion, our experience supports the possibility of patients in stable remission discontinuing eculizumab treatment, but this decision may depend on the identified gene mutation. Such a policy also requires the full commitment of the patients, who need to be clearly informed about the risks involved and the importance of strict urine dipstick monitoring, particularly during acute intercurrent diseases. Better understanding of genotype/phenotype correlations in large data sets will certainly provide important clues about how to manage eculizumab maintenance treatment in such a way as to reduce the risks and costs of treatment while maximizing the benefits.
ACKNOWLEDGEMENTS Support: This study was supported by a research grant provided by “Progetto Alice – Associazione per la lotta alla SEU.” Financial Dislcosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Kavanagh D, Richards A, Atkinson J. Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med. 2008;59:293-309. 2. Mache CJ, Acham-Roschitz B, Frémeaux-Bacchi V, et al. Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009;4(8):1312-1316. 3. Châtelet V, Lobbedez T, Frémeaux-Bacchi V, Ficheux M, Ryckelynck JP, Hurault de Ligny B. Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report. Transplant Proc. 2010;42(10):4353-4355. 4. Scheiring J, Rosales A, Zimmerhackl LB. Clinical practice. Today’s understanding of the haemolytic uraemic syndrome. Eur J Pediatr. 2010;169(1):7-13. 5. Constantinescu AR, Bitzan M, Weiss LS, et al. Nonenteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43(6):976-982. 6. Taylor CM, Machin S, Wigmore SJ, Goodship TH; Working Party From the Renal Association, the British Committee for
4
Standards in Haematology and the British Transplantation Society. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol. 2010;148(1):37-47. 7. Rees L. Atypical HUS: time to take stock of current guidelines and outcome measures? Pediatr Nephrol. 2013;28(5): 675-677. 8. Ohanian M, Cable C, Halka K. Reduced dose maintenance eculizumab in atypical hemolytic uremic syndrome (aHUS): an update on a previous case report. Clin Pharmacol. 2011;3:45-50. 9. Moore I, Strain L, Pappworth I, et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood. 2010;115(2):379-387. 10. Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(4):345-357. 11. Kavanagh D, Goodship TH. Atypical hemolytic uremic syndrome. Curr Opin Hematol. 2010;17(5):432-438. 12. Skerka C, Józsi M, Zipfel PF, Dragon-Durey MA, Fremeaux-Bacchi V. Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost. 2009;101(2):227-232. 13. Fremeaux-Bacchi V. Treatment of atypical uremic syndrome in the era of eculizumab. Clin Kidney J. 2012;5:4-6. 14. Besbas N, Gulhan B, Karpman D, et al. Neonatal onset atypical hemolytic uremic syndrome successfully treated with eculizumab. Pediatr Nephrol. 2013;28(1):155-158. 15. Köse O, Zimmerhackl LB, Jungraithmayr T, Mache C, Nürnberger J. New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin Thromb Hemost. 2010;36(6):669-672. 16. FDA. News release September 23, 2011. http://www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm272990.htm. Accessed March 13, 2014. 17. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Frémeaux-Bacchi V, Legendre C. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011;7(1):23-35. 18. Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360(5):544-546. 19. Nürnberger J, Philipp T, Witzke O, et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360(5): 542-544. 20. Vilalta R, Lara E, Madrid A, et al. Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome. Pediatr Nephrol. 2012;27(12):2323-2326. 21. European Medicines Agency. Soliris (online). http://www. ema.europa.eu/ema/index.jsp?curl5pages/medicines/human/medici nes/000791/human_med_001055.jsp&mid5WC0b01ac058001d24 (2012). Accessed March 13, 2014. 22. Carr R, Cataland SR. Relapse of aHUS after discontinuation of therapy with eculizumab in a patient with aHUS and factor H mutation. Ann Hematol. 2013;92(6):845-846. 23. Mache CJ, Acham-Roschitz B, Fremeaux-Bacchi V, et al. Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009;4(8):1312-1316. 24. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Fremeaux-Bacchi V, Legendre C. New insights into post-renal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011;7(1):23-35. 25. Cayci FS, Cakar N, Hancer VS, Uncu N, Acar B, Gur G. Eculizumab therapy in a child with hemolytic uremic syndrome and CFI mutation. Pediatr Nephrol. 2012;27(12):2327-2331.
Am J Kidney Dis. 2014;-(-):---
Eculizumab Treatment Discontinuation in aHUS 26. Gulleroglu K, Fidan K, Hançer VS, Bayrakci U, Baskin E, Soylemezoglu O. Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab. Pediatr Nephrol. 2013;28(5):827-830. 27. Struijk GH, Bouts AH, Rijkers GT, Kuin EA, ten Berge IJ, Bemelman FJ. Meningococcal sepsis complicating eculizumab treatment despite prior vaccination. Am J Transplant. 2013;13(3):819-820. 28. Ram S, Lewis LA, Rice PA. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev. 2010;23:740-780. 29. Ariceta G, Besbas N, Johnson S, et al; European Paediatric Study Group for HUS. Guideline for the investigation and initial
Am J Kidney Dis. 2014;-(-):---
therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24(4):687-696. 30. Zuber J, Fakhouri F, Roumenina LT, Loirat C, FrémeauxBacchi V; French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012;8(11):643-657. 31. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. 32. Zuber J, Le Quintrec M, Krid S, et al; French Study Group for Atypical HUS. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012;12(12):3337-3354.
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