A randomized trial of factor VIII and neutralizing antibodies in hemophilia A

F. Peyvandi, P. M. Mannucci, I. Garagiola, A. El-Beshlawy, M. Elalfy, V. Ramanan, P. Eshghi, S. Hanagavadi, R. Varadarajan, M. Karimi, M. V. Manglani, C. Ross, G. Young, T. Seth, S. Apte, D. M. Nayak, E. Santagostino, M. E. Mancuso, A. C. Sandoval Gonzalez, J. N. MahlanguS. Bonanad Boix, M. Cerqueira, N. P. Ewing, C. Male, T. Owaidah, Soto V. Arellano, N. L. Kobrinsky, S. Majumdar, R. Perez Garrido, A. Sachdeva, M. Simpson, M. Thomas, E. Zanon, B. Antmen, K. Kavakli, M. J. Manco-Johnson, M. Martinez, E. Marzouka, M. G. Mazzucconi, D. Neme, A. Palomo Bravo, R. Paredes Aguilera, A. Prezotti, K. Schmitt, B. M. Wicklund, B. Zulfikar, F. R. Rosendaal

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII.

Original languageEnglish
Pages (from-to)2054-2064
Number of pages11
JournalNew England Journal of Medicine
Volume374
Issue number21
DOIs
Publication statusPublished - 26-05-2016

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Factor VIII
Hemophilia A
Neutralizing Antibodies
Confidence Intervals
Incidence
Isoantibodies
Random Allocation
Proportional Hazards Models
Therapeutics

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Peyvandi, F., Mannucci, P. M., Garagiola, I., El-Beshlawy, A., Elalfy, M., Ramanan, V., ... Rosendaal, F. R. (2016). A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. New England Journal of Medicine, 374(21), 2054-2064. https://doi.org/10.1056/NEJMoa1516437
Peyvandi, F. ; Mannucci, P. M. ; Garagiola, I. ; El-Beshlawy, A. ; Elalfy, M. ; Ramanan, V. ; Eshghi, P. ; Hanagavadi, S. ; Varadarajan, R. ; Karimi, M. ; Manglani, M. V. ; Ross, C. ; Young, G. ; Seth, T. ; Apte, S. ; Nayak, D. M. ; Santagostino, E. ; Mancuso, M. E. ; Sandoval Gonzalez, A. C. ; Mahlangu, J. N. ; Bonanad Boix, S. ; Cerqueira, M. ; Ewing, N. P. ; Male, C. ; Owaidah, T. ; Arellano, Soto V. ; Kobrinsky, N. L. ; Majumdar, S. ; Perez Garrido, R. ; Sachdeva, A. ; Simpson, M. ; Thomas, M. ; Zanon, E. ; Antmen, B. ; Kavakli, K. ; Manco-Johnson, M. J. ; Martinez, M. ; Marzouka, E. ; Mazzucconi, M. G. ; Neme, D. ; Palomo Bravo, A. ; Paredes Aguilera, R. ; Prezotti, A. ; Schmitt, K. ; Wicklund, B. M. ; Zulfikar, B. ; Rosendaal, F. R. / A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. In: New England Journal of Medicine. 2016 ; Vol. 374, No. 21. pp. 2054-2064.
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abstract = "BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8{\%} (95{\%} confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5{\%} (95{\%} CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6{\%} (95{\%} CI, 11.2 to 26.0) and 28.4{\%} (95{\%} CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87{\%} higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95{\%} CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95{\%} CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95{\%} CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95{\%} CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII.",
author = "F. Peyvandi and Mannucci, {P. M.} and I. Garagiola and A. El-Beshlawy and M. Elalfy and V. Ramanan and P. Eshghi and S. Hanagavadi and R. Varadarajan and M. Karimi and Manglani, {M. V.} and C. Ross and G. Young and T. Seth and S. Apte and Nayak, {D. M.} and E. Santagostino and Mancuso, {M. E.} and {Sandoval Gonzalez}, {A. C.} and Mahlangu, {J. N.} and {Bonanad Boix}, S. and M. Cerqueira and Ewing, {N. P.} and C. Male and T. Owaidah and Arellano, {Soto V.} and Kobrinsky, {N. L.} and S. Majumdar and {Perez Garrido}, R. and A. Sachdeva and M. Simpson and M. Thomas and E. Zanon and B. Antmen and K. Kavakli and Manco-Johnson, {M. J.} and M. Martinez and E. Marzouka and Mazzucconi, {M. G.} and D. Neme and {Palomo Bravo}, A. and {Paredes Aguilera}, R. and A. Prezotti and K. Schmitt and Wicklund, {B. M.} and B. Zulfikar and Rosendaal, {F. R.}",
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Peyvandi, F, Mannucci, PM, Garagiola, I, El-Beshlawy, A, Elalfy, M, Ramanan, V, Eshghi, P, Hanagavadi, S, Varadarajan, R, Karimi, M, Manglani, MV, Ross, C, Young, G, Seth, T, Apte, S, Nayak, DM, Santagostino, E, Mancuso, ME, Sandoval Gonzalez, AC, Mahlangu, JN, Bonanad Boix, S, Cerqueira, M, Ewing, NP, Male, C, Owaidah, T, Arellano, SV, Kobrinsky, NL, Majumdar, S, Perez Garrido, R, Sachdeva, A, Simpson, M, Thomas, M, Zanon, E, Antmen, B, Kavakli, K, Manco-Johnson, MJ, Martinez, M, Marzouka, E, Mazzucconi, MG, Neme, D, Palomo Bravo, A, Paredes Aguilera, R, Prezotti, A, Schmitt, K, Wicklund, BM, Zulfikar, B & Rosendaal, FR 2016, 'A randomized trial of factor VIII and neutralizing antibodies in hemophilia A', New England Journal of Medicine, vol. 374, no. 21, pp. 2054-2064. https://doi.org/10.1056/NEJMoa1516437

A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. / Peyvandi, F.; Mannucci, P. M.; Garagiola, I.; El-Beshlawy, A.; Elalfy, M.; Ramanan, V.; Eshghi, P.; Hanagavadi, S.; Varadarajan, R.; Karimi, M.; Manglani, M. V.; Ross, C.; Young, G.; Seth, T.; Apte, S.; Nayak, D. M.; Santagostino, E.; Mancuso, M. E.; Sandoval Gonzalez, A. C.; Mahlangu, J. N.; Bonanad Boix, S.; Cerqueira, M.; Ewing, N. P.; Male, C.; Owaidah, T.; Arellano, Soto V.; Kobrinsky, N. L.; Majumdar, S.; Perez Garrido, R.; Sachdeva, A.; Simpson, M.; Thomas, M.; Zanon, E.; Antmen, B.; Kavakli, K.; Manco-Johnson, M. J.; Martinez, M.; Marzouka, E.; Mazzucconi, M. G.; Neme, D.; Palomo Bravo, A.; Paredes Aguilera, R.; Prezotti, A.; Schmitt, K.; Wicklund, B. M.; Zulfikar, B.; Rosendaal, F. R.

In: New England Journal of Medicine, Vol. 374, No. 21, 26.05.2016, p. 2054-2064.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A randomized trial of factor VIII and neutralizing antibodies in hemophilia A

AU - Peyvandi, F.

AU - Mannucci, P. M.

AU - Garagiola, I.

AU - El-Beshlawy, A.

AU - Elalfy, M.

AU - Ramanan, V.

AU - Eshghi, P.

AU - Hanagavadi, S.

AU - Varadarajan, R.

AU - Karimi, M.

AU - Manglani, M. V.

AU - Ross, C.

AU - Young, G.

AU - Seth, T.

AU - Apte, S.

AU - Nayak, D. M.

AU - Santagostino, E.

AU - Mancuso, M. E.

AU - Sandoval Gonzalez, A. C.

AU - Mahlangu, J. N.

AU - Bonanad Boix, S.

AU - Cerqueira, M.

AU - Ewing, N. P.

AU - Male, C.

AU - Owaidah, T.

AU - Arellano, Soto V.

AU - Kobrinsky, N. L.

AU - Majumdar, S.

AU - Perez Garrido, R.

AU - Sachdeva, A.

AU - Simpson, M.

AU - Thomas, M.

AU - Zanon, E.

AU - Antmen, B.

AU - Kavakli, K.

AU - Manco-Johnson, M. J.

AU - Martinez, M.

AU - Marzouka, E.

AU - Mazzucconi, M. G.

AU - Neme, D.

AU - Palomo Bravo, A.

AU - Paredes Aguilera, R.

AU - Prezotti, A.

AU - Schmitt, K.

AU - Wicklund, B. M.

AU - Zulfikar, B.

AU - Rosendaal, F. R.

PY - 2016/5/26

Y1 - 2016/5/26

N2 - BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII.

AB - BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII.

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U2 - 10.1056/NEJMoa1516437

DO - 10.1056/NEJMoa1516437

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Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. New England Journal of Medicine. 2016 May 26;374(21):2054-2064. https://doi.org/10.1056/NEJMoa1516437