Evaluation of safety and effectiveness of factor VIII treatment in haemophilia A patients with low titre inhibitors or a personal history of inhibitor

 

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Summary

There is no prospective evidence on inhibitor recurrence among haemophilia A patients with low titre inhibitors or history of inhibitors, and whether or how therapeutic choices affect the risk of recurrence. The aims of this study were to synthesise safety data in patients with moderate-severe haemophilia A and with low titre inhibitors or inhibitor history enrolled in the rAHF PFM (ADVATE) – Post-Authorization Safety Studies (ADVATE-PASS) international programme. The study was conducted in clinics participating to the ADVATE PASS programme. The patient population consisted of patients entering the studies with low titre (≤5 BU) inhibitors or a positive personal history of inhibitors. Patients on Immune Tolerance Induction at study entry were excluded. Primary outcome was new or recurrent inhibitor titre > 5 BU. Secondary outcomes were any increase of inhibitor titre not reaching 5 BU; any unexplained change in treatment regimen. Primary analysis was done by two-stage random effects meta-analysis. Secondary analysis was done by a hierarchical Bayesian random effects logistic model. A total of 219 patients from seven studies were included. Of these 214 (97.7 %) patients had been previously treated for more than 50 exposure days. Two hundred ten patients had positive history for inhibitors, nine a baseline measurable titre. No patient presented a primary outcome event (95 % confidence interval [CI] 0–1.6 %). Six patients with previous history developed a low titre recurrence (overall rate 2.2, 95 %CI 0–4.8 %). When any increase of inhibitor titre or any treatment change was accounted for, overall 3.7 % (95 % CI 0 %-8.0 %) of patients experienced the outcome. In conclusion, the observed rate of events does not support the definition of this population as at high risk for inhibitor development.

• References

• 1 Hay CR, Palmer B, Chalmers E. et al. United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO).. Incidence of factor VIII inhibitors throughout life in severe haemophilia A in the United Kingdom. Blood 2011; 117: 6367-6370.
  CrossrefPubMedGoogle Scholar
• 2 Caram C, de Souza RG, de Sousa JC. et al. The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction. Thromb Haemost 2011; 105: 59-65.
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Tagariello G, Iorio A, Matino D. et al. High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia a patients not undergoing immunotolerance. J Hematol Oncol 2013; 06: 63.
  CrossrefPubMedGoogle Scholar
• 4 Gouw SC, van den Berg HM. The multifactorial etiology of inhibitor development in haemophilia: genetics and environment. Semin Thromb Haemost 2009; 35: 723-734.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Bray GL, Gomperts ED, Courter S. et al. A Multicenter Study of Recombinant Factor VIII (Recombinate): Safety, Efficacy, and Inhibitor Risk in Previously Untreated Patients with Hemophilia. A Blood 1994; 83: 2428-2435.
  PubMedGoogle Scholar
• 6 Lusher JM. First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Haemost 2002; 28: 273-276.
  Article in Thieme ConnectPubMedGoogle Scholar
• 7 Mahlangu JN, Gilham A. Medical and Scientific Advisory Council of the South African Haemophilia Foundation. Guideline for the treatment of haemophilia in South Africa. S Afr Med J 2008; 98: 126-140.
  PubMedGoogle Scholar
• 8 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al. Treatment Guidelines Working Group on Behalf of The World Federation Of Haemophilia.. Guidelines for the management of haemophilia. Haemophilia 2013; 19: e1-47.
  CrossrefPubMedGoogle Scholar
• 9 Gringeri A, Mannucci PM. Italian Association of Haemophilia Centres. Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors. Haemophilia 2005; 11: 611-619.
  CrossrefPubMedGoogle Scholar
• 10 Kempton CL, White GC. 2nd. How we treat a haemophilia A patient with a factor VIII inhibitor. Blood 2009; 113: 11-17.
  CrossrefPubMedGoogle Scholar
• 11 BAX 855 – NCT01736475 – clinicaltrials.gov last assessed August 29, 2014.
  PubMed
• 12 Bay-94 – NCT01580293 – clinicaltrials.gov last assessed August 29, 2014.
  PubMed
• 13 Marcucci M, Mancuso ME, Santagostino E. et al. Type and intensity of FVIII exposure on inhibitor development in PUPs with haemophilia A. A patient level meta-analysis. Thromb Haemost 2015; 113: 911-1157.
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 Mahlangu J, Powell JS, Ragni MV. et al. A-LONG Investigators.. Phase 3 study of recombinant factor VIII Fc fusion protein in severe haemophilia A. Blood 2014; 123: 317-325.
  CrossrefPubMedGoogle Scholar
• 15 Manco-Johnson MJ, Kempton CL, Reding MT. et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe haemophilia A (SPINART). J Thromb Haemost 2013; 11: 1119-1127.
  CrossrefPubMedGoogle Scholar
• 16 Iorio A, Halimeh S, Holzhauer S. et al. Rate of inhibitor development in previously untreated haemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 08: 1256-1265.
  CrossrefPubMedGoogle Scholar
• 17 Gouw SC, van der Bom JG, Ljung R. et al. PedNet and RODIN Study Group.. Factor VIII products and inhibitor development in severe haemophilia A. N Engl J Med 2013; 368: 231-239.
  CrossrefPubMedGoogle Scholar
• 18 Tarantino MD, Collins PW, Hay CR. et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004; 10: 428-437.
  CrossrefPubMedGoogle Scholar
• 19 Sutton AJ, Abrams KR. Bayesian methods in meta-analysis and evidence synthesis. Stat Methods Med Res 2001; 10: 277-303.
  CrossrefPubMedGoogle Scholar
• 20 Ashby D, Smith AF. Evidence-based medicine as Bayesian decision-making. Stat Med 2000; 19: 3291-3305.
  CrossrefPubMedGoogle Scholar
• 21 Kreuz W, Gill JC, Rothschild C. et al. International Kogenate-FS Study Group.. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of an international clinical investigation. Thromb Haemost 2005; 93: 457-467.
  Article in Thieme ConnectPubMedGoogle Scholar
• 22 Auerswald G, Thompson AA, Recht M. et al. Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A. Thromb Haemost 2012; 107: 1072-1082.
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Lusher JM. First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Haemost 2002; 28: 273-276.
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Tarantino MD, Collins PW, Hay CR. et al. RAHF-PFM Clinical Study Group.. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004; 10: 428-437.
  CrossrefPubMedGoogle Scholar
• 25 Lusher JM, Lee CA, Kessler CM. et al. ReFacto Phase 3 Study Group.. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 09: 38-49.
  PubMedGoogle Scholar
• 26 Valentino LA, Mamonov V, Hellmann A. et al. Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10: 359-367.
  CrossrefPubMedGoogle Scholar
• 27 Recht M, Nemes L, Matysiak M. et al. Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor VIII. Haemophilia 2009; 15: 869-880.
  CrossrefPubMedGoogle Scholar
• 28 Blanchette VS, Shapiro AD, Liesner RJ. et al. rAHF-PFM Clinical Study Group.. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost 2008; 06: 1319-1326.
  CrossrefPubMedGoogle Scholar
• 29 Kulkarni R, Karim FA, Glamocanin S. et al. Results from a large multinational clinical trial (guardian™3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics. Haemophilia 2013; 19: 698-705.
  CrossrefPubMedGoogle Scholar
• 30 Valentino LA, Mamonov V, Hellmann A. et al. Prophylaxis Study Group.. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in haemophilia A management. J Thromb Haemost 2012; 10: 359-367.
  CrossrefPubMedGoogle Scholar
• 31 Matino D, Lillicrap D, Astermark J. et al. Switching clotting factor concentrates: considerations in estimating the risk of immunogenicity. Haemophilia 2014; 20: 200-206.
  CrossrefPubMedGoogle Scholar
• 32 Iorio A, Marcucci M, Cheng J. et al. Patient data meta-analysis of Post-Authorization Safety Surveillance (PASS) studies of haemophilia A patients treated with rAHF-PFM. Haemophilia 2014; 20: 777-783.
  CrossrefPubMedGoogle Scholar
• 33 White GC, McMillan CW, Kingdon HS. et al. Use of recombinant antihaemophilic factor in the treatment of two patients with classic haemophilia. N Engl J Med 1989; 320: 166-170.
  CrossrefPubMedGoogle Scholar