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  • American Society of Hematology  (4)
  • 1
    Online-Ressource
    Online-Ressource
    Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial)
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 274-274
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 274-274
    Kurzfassung: BACKGROUND: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia characterized by hemagglutination and complement-mediated extra- and intravascular hemolysis. Conventional therapeutic approaches, such as corticosteroids, intravenous immunoglobulin G, alkylating agents or other immunosuppressive drugs, are largely ineffective, and the therapeutic efficacy of rituximab is limited. Successful treatment of a patient with CAD with the terminal complement inhibitor eculizumab reported by us previously (Röth et al., Blood 2009) prompted us to test this novel approach in a larger number of patients. PATIENTS and METHODS: We conducted a prospective, controlled, non-randomized, multicenter phase II trial with pre- and post-treatment comparison. Inclusion criteria were symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level ≥ 2 x upper limit of normal and a cold agglutinin titer 〉 64 at 4°C. Eculizumab was given by intravenous infusion at 600 mg weekly for 4 weeks, followed 1 week later by a 900 mg dose and then 900 mg every other week through week 26. Two weeks before the first dose patients received vaccination against N. meningitidis. The primary endpoint was LDH level, secondary endpoints included transfusion requirements, parameters of intravascular hemolysis, quality of life, 6-minute walk test (6MWT), circulatory symptoms and thrombosis. The analysis was performed in the intent-to-treat population. Missing data were replaced by carrying the last observation forward. The trial was registered at http://clinicaltrials.gov as NCT01303952. RESULTS: Between 2011 and 2014 13 treatment-naïve or pretreated patients with CAD were enrolled. The median age was 74 years (range: 64 - 80), with a male-to-female ratio of 3 to 10. After treatment with eculizumab the LDH decreased from a median pre-treatment level of 572 U/L (mean ± standard deviation: 670 ± 300 U/L) by an average of 56% to a median end-of-treatment level of 327 U/L (400 ± 279 U/L; p = 0.0215, Wilcoxon signed-rank test). This was accompanied by a reduction in transfusion requirement from a median of 4.0 red blood cell units per patient in the 12-month period preceding participation in the study to 0.0 units during treatment with eculizumab. In 9 patients, transfusion requirements decreased during eculizumab therapy, in 3 patients, transfusions were required neither before nor during the study, and in one patient, transfusion requirement deteriorated (p = 0.0215, Exact McNemar's test). The result of the 6MWT improved from a median of 358 m at baseline to a median of 420 m at the end of treatment (p = 0.078). Questionnaires for quality of life showed no significant changes. During the enrollment phase, 7 thromboembolic events including 1 pulmonary embolism were recorded in a total of 4 patients; by contrast, no thromboembolic events were observed during treatment with eculizumab. A total of 37 adverse events were reported of which one was considered as probably related to eculizumab (pneumonia, patient recovered). All in all, 57% of adverse events were classified as unrelated, 5% as unlikely to be related, 32% as possibly related, and 3% as probably related to treatment. There were 4 serious adverse events. CONCLUSIONS: Treatment with eculizumab was safe and well tolerated in patients with CAD. It resulted in a statistically significant reduction in hemolysis and transfusion requirements and appeared to have a favorable impact on thromboembolic complications. The results of this trial support the notion that terminal complement activation is a relevant mediator of erythrocyte destruction in CAD. Disclosures Röth: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding. Off Label Use: Use of eculizumab in CAD. Bommer:Alexion Pharmaceuticals: Honoraria. Hüttmann:Celgene: Other: Travel support, Speakers Bureau; Takeda: Consultancy, Other: Travel support; Gilead: Consultancy; Amgen: Consultancy, Research Funding; Roche: Research Funding. Schrezenmeier:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dührsen:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.274.274
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2015
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Serologic Response to Meningococcal Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) for the Chronic Treatment with the Terminal Complement Inhibitor Eculizumab
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 4380-4380
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4380-4380
    Kurzfassung: BACKGROUND: Eculizumab is indicated for the therapy of patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). Due to inhibition of terminal complement cascade, patients on eculizumab are susceptible to N. meningitids infections (0.48 cases per 100-patient years). The two mainstays to reduce the risk of infection are vaccination at least two weeks prior to treatment and antibiotic prophylaxis. PATIENTS/METHODS: In this retrospective study serologic response was analyzed after vaccination with a meningococcal vaccine in PNH patients (n=32) by measuring serum bactericidal antibody titers with external rabbit complement (rSBA) against meningococci serogroups A, C, W and Y. 78.1% of the patients (25/32) received a tetravalent conjugate vaccine, while 6.3% (2/32) received an unconjugated polysaccharide vaccine. In 9.4% (n=3) the type of vaccine administrated was not available. Serologic response was defined by an rSBA titer ≥1:8. In 23 patients the corresponding rSBA titers were available. 39.1% (9/23) had been vaccinated more than once due to chronic eculizumab treatment. RESULTS: Overall serologic responses independent of the time of observation for the meningococcal serogroups were: A: 78.3%, C: 86.9%, W: 47.8%, Y: 69.6%. rSBA titers varied significantly for the different time points [≤2 months (n=1): A: 100%, C: 100%, W: 100%, Y: 100%; ≤4- 〈 6 months (n=4): A: 75%, C: 100%, W: 75%, Y: 75%; ≥6- 〈 12 months (n=5): A: 60%, C: 40%, W: 0%, Y: 40%; ≥ 12-36 months (n=13): A: 84.6%, C: 100%, W: 53.8%, Y: 76.9%]. In 5 patients (15.6%) rSBA titers against 3 serogroups were 〈 1:8, while 5 other patients (15.6%) had rSBA titers 〈 1:8 against 2 serogroups at the same time. Serologic response after vaccination with an unconjugated vaccine even for the third time (n=1) prior to observation due to chronic therapy was identical to patients who had been vaccinated only once, supporting a non-immunological memory post vaccination with an unconjugated vaccine. No meningococcal infections have been observed in the analyzed cohort of eculizumab treated PNH patients so far. SUMMARY/CONCLUSIONS: Efficiency of meningococcal vaccines for the different serotypes varies significantly and serological response analyses are very useful. Revaccination with the tetravalent conjugate vaccine (Menveo®) every 3 years is recommended or should be based on the individual response. However, physicians and patients must be vigilant for meningococcal infections at all times. Furthermore, stand-by therapy with ciprofloxacin 750 mg p.o. in case of signs of meningococcal infection and immediate medical evaluation and treatment is recommended. The availability of a novel vaccine covering the B-strain (Bexsero®) may further reduce the risk of an infection. Disclosures Roeth: Alexion: Consultancy, Honoraria, Research Funding. Duehrsen:Alexion: Honoraria.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.4380.4380
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2014
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Persisting Hyperbilirubinemia in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Chronically Treated with Eculizumab: The Role of Hepatocanalicular Transport Variants
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 940-940
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 940-940
    Kurzfassung: BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is caused by an acquired mutation in the phosphatidylinositol (GPI)-anchors. The lack of GPI-anchored proteins on the surface of affected red blood cells (RBCs) results in complement mediated chronic intravascular hemolysis. The monoclonal anti-C5 antibody eculizumab protects PNH RBCs by blocking the terminal complement cascade. Eculizumab treated PNH patients show a dramatic decrease of LDH and bilirubin, however few patients remain hyperbilirubinemic, eventually indicating an inadequate response. Hepatocanalicular transporters are rate-limiting in the process of bile formation, and mutations in the genes encoding these transporters cause intrahepatic cholestasis. PATIENTS and METHODS: Mutation analysis regarding hepatobiliary transporter and nuclear receptor defects (ABCB4, ABCB11, ATP8B1, NR1H4) were performed in eight [75% (6/8) male; mean age, 40 years (range 25 - 70 years)] out of the currently 141 patients with PNH/-clone at our department due to a persistent (isolated) increase in total serum bilirubin (median 4.5 mg/dL; range 3.0 - 8.5) during chronic treatment with eculizumab (LDH: median 274 U/L; range 172 - 836) and normal or slightly increased aminotransferases. Clinical symptoms resembled those of hyperbilirubinemia including jaundice. Median clone size of GPI-deficient granulocytes (FLAER) was 98.1% (range 79.0 - 99.5%), with a median observation time of 56.4 months (range 10.6 - 82.7 months). All patients were treated according to the current German PNH guidelines. RESULTS: Both homozygous and heterozygous procholestatic variants in the ABCB4, ABCB11 and ATP8B1 genes, encoding canalicular transporters, were identified in the studied patients, and all patients carried the common ABCB4 c.787 A 〉 T polymorphism (Table 1). None of the patients were tested positive for the common mutation c.-1g 〉 t of the central bile acid sensor NR1H4. Table 1. Hepatobiliary transporter gene variants in PNH patients (n=8) Variant Pat. 1 Pat. 2 Pat. 3 Pat. 4 Pat. 5 Pat. 6 Pat. 7 Pat. 8 ABCB4 c.504T 〉 C (rs1202283) HOM HET HET HOM neg. neg. HOM neg. ABCB4 c.787A 〉 T (rs2109505) HOM HOM HOM HOM HOM HOM HOM HET ABCB11 p.A444V (rs2287622) HOM HET neg. HET neg. neg. HET HOM ABCB11 c.3084A 〉 G (rs497692) HET HET HET neg. HOM HET HOM HET ATP8B1 p.R952Q (rs12968116) HOM neg. HET HET neg. HET neg. neg. NR1H4 (FXR) c.-1 g 〉 t (rs56163822) neg. neg. neg. neg. neg. neg. neg. neg. Pat.: Patient; HOM: homozygous; HET: heterozygous; neg.: negative Routine sonographic follow-up examinations were performed in 75% of the patients (6/8) ruling out post-hepatic cholestasis. In three patients (pat. 2, 3 and 4), a cholecystectomy due to symptomatic cholelithiasis had been performed prior to diagnosis of PNH, whereas in one patient the diagnosis of a persistent, asymptomatic cholelithiasis (pat. 6) was made. A chronic (active) or recently acquired viral hepatitis was ruled out in all patients. Lab parameters were consistent with an isolated persistent increase in total serum bilirubin, despite normal (7/8) or slightly elevated transaminases (1/8; pat. 6) throughout observation time. SUMMARY/CONCLUSIONS: This is the first report of mutations in hepatobiliary transporter genes predisposing to intrahepatic cholestasis in PNH patients. Therefore, persisting hyperbilirubinemia in PNH patients chronically treated with eculizumab might not be due to an insufficient response to eculizumab but due to bile acid transporter variants and ongoing extravascular hemolysis. Patients should be tested for and possible therapeutic agents established in the management include ursodeoxycholic acid, promoting bile flow, and rifampicin, accelerating hepatic detoxification and excretion of bilirubin and bile acids. Our data warrant further studies concerning the role of hepatobiliary transporter variants in PNH patients in order to determine their clinical significance. Disclosures Dührsen: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Röth:Geron: Research Funding; Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.940.940
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2015
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    Serologic Response to Meningococcal Vaccination in Patients with Cold Agglutinin Disease (CAD) in the New Era of Complement Inhibition
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3817-3817
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3817-3817
    Kurzfassung: BACKGROUND: Cold agglutinin disease (CAD) is an ultra-rare and potentially life-threatening, acquired autoimmune hemolytic anemia. It is characterized by hemagglutination and hemolysis due to immunoglobulin-mediated (usually IgMᴋ) classic complement pathway activation aggravated by infections and exposure to cold environmental temperatures. As conventional approaches are largely ineffective or short term in controlling hemolysis, complement inhibition (CI) (eculizumab-C5, BIVV009-C1s, and APL-2-C3) represents a novel and promising treatment option in these patients (pts). However, due to inhibition of complement cascade, pts are susceptible to encapsulated bacteria, especially N. meningitidis. Therefore, meningococcal vaccination is mandatory on CI to reduce the risk of infection. PATIENTS/METHODS: In this systematic study serologic response to the quadrivalent meningococcal polysaccharide conjugate vaccine (Menveo®) in pts with CAD (n=9; 8 females; mean age, 73 yrs (range 64-80 yrs)) was analyzed prior to vaccination and initiation of CI (eculizumab, DECADE Trial (Röth et. al, Blood 2015; 126:274)) and after vaccination at two distinct time intervals (median, 42 days (range 18-60 days) and median, 193 days (range 156-200 days) by measuring serum bactericidal antibody titers with external rabbit complement (rSBA) against meningococcal serogroups A, C, W135 and Y. In one pt rSBA titers were not assessable at the first interval following vaccination. By definition, serologic protection is defined by a rSBA titer ≥1:8 or a fourfold rise pre- to postvaccination. RESULTS: Serologic response in terms of protective rSBA titers to Menveo® after vaccination varied in CAD pts for the meningococcal serogroups and the different time points: A 25% (2/8), C 25% (2/8), W135 50% (4/8), Y 62% (5/8) at first observation compared to: A 0% (0/9), C 22% (2/9), W135 33% (3/9), Y 44% (4/9) at second rSBA titer measurement, reflecting an early decline in protective rSBA titers to non-protective titers over time (Fig. 1). However, no meningococcal infections have been observed in the analyzed cohort under CI. In pts. with a fourfold rise in rSBA titers pre- to postvaccination the beneficial role of conjugated meningococcal vaccinations in contrast to unconjugated vaccines, resembled by increased immunity with booster vaccinations and an anticipated enhanced duration of protection, might further be supported. SUMMARY/CONCLUSIONS: Efficiency of meningococcal vaccines for the different serogroups in CAD pts varies significantly and serological response analyses, especially in the currently recruiting CAD-Trials (BIVV009 and APL-2) addressing CI, are useful. By now, revaccination with the tetravalent conjugate vaccine (Menveo®) every 3 years is recommended. However, the associated risks with long-term CI are presently unknown and might be individually based on serologic response analyses to vaccination, which might even imply additional booster vaccination in pts on chronic CI. Physicians and pts must be vigilant for meningococcal infections at all times. A stand-by therapy with ciprofloxacin 750 mg p.o. in case of signs of meningococcal infection should be recommended with immediate medical evaluation and treatment. The availability of the novel vaccines covering serogroup B (Bexsero®, Trumenba®) may further reduce the risk of infections and should be mandatory in these pts, despite no current test exists to measure serologic response to meningococcal serogroup B on chronic CI. Disclosures Duehrsen: AbbVie: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria. Röth:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-118968
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2018
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
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