Search

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8genotypes than in patients with high-risk F8genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8mutations.

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients’ F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A.

Santagostino: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Male:SOBI: Speakers Bureau; Shire: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liesner:Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Sobi: Speakers Bureau; Bayer: Consultancy, Research Funding; Roche: Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Carcao:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:CSL Behring: Research Funding; Sobi: Research Funding; Bayer: Research Funding. Álvarez-Roman:Shire: Consultancy; NovoNordisk: Consultancy; SOBI: Consultancy. Koenigs:Gilead: Research Funding; CSL Behring: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Intersero: Research Funding; Bioverativ: Consultancy; Roche/Chugai: Consultancy; EU (IMI, FP7): Research Funding; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding; Novo Nordisk: Consultancy, Speakers Bureau; Biotest: Research Funding, Speakers Bureau; Jansen: Research Funding.

Introduction.In patients with hemophilia treated with factor VIII products, the development of inhibitory antibodies poses the largest safety risk. Especially during the first 50 exposure days (EDs), up to 37% of patients with severe hemophilia A have been reported to develop an inhibitor. To study neo-immunogenicity of products and new treatment strategies, patients have been distinguished into previously untreated (PUPs) and previously treated patients (PTPs); the latter defined as patients treated for more than 150 EDs. The number of 150 EDs was established in the eighties during a time when most patients received on-demand treatment and testing for inhibitors was not frequently performed. More recent studies on inhibitor incidence in PUPs with severe hemophilia A report that 50% of inhibitors develop within 14-15 EDs, however the cut-off number of EDs for a PUP to become a PTP is not well defined.

Mancuso: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.

▪

A 40 year-old Caucasian patient with severe familial hemophilia A (FVIII <1%) related to an intron 22 inversion developed at the age of 2 a high-responding inhibitor. His elder brother also suffers from hemophilia A with high-responding inhibitor. Until 2000, the patient had been treated either using activated prothrombin complex concentrates (Autoplex® and Feiba®) or factor VIII (FVIII) concentrates of human (1983) and porcine origin (1992), resulting respectively in an inhibitor level rise at 360 Bethesda Units (BU) and 1800 BU. Between 2000 and 2003, the patient received exclusively recombinant activated Factor VII (NovoSeven®), and his inhibitor levels stabilized at a plateau of 15–20 BU. Between 2000 and 2003, several life or function threatening bleeding episodes occurred, such as hematomas of the iliopsoas muscles, spinal cord hematoma with transient paraplegia. Furthermore, due to hemarthroses the patient was confined to a wheelchair. Given the major impact of the inhibitor on the patient’s functional prognosis, life expectancy and quality of life, immune tolerance (IT) treatment was initiated, despite the high risk of failure (initiation 36 years after inhibitor onset, historical peak titer at 1800 BU, persistence of a plateau of 15–20 BU despite the absence of any stimulation with FVIII within the 3 last years). It started with an immunosuppressive drug, mycofenolate mofetil (Cellcept®) first given in may 2003 (no effect alone on inhibitor titer) and then in November 2003, infusions of a FVIII concentrate rich in von Willebrand factor, Factane® (LFB, Les Ulis, France) using 12,000 IU/day (150 IU/kg) of FVIII. The inhibitor peaked at 520 BU on D19 and was 0.5 BU by May 2004. Thus, the FVIII dosage was progressively reduced to 7000 IU/day. In July 2005, 24 hours after a 7000 IU FVIII infusion, inhibitor level was 0.7 BU, the residual FVIII level was 0.04IU/ml with a recovery of FVIIIc of 1.37%/IU/kg infused and a half-life of 4.9 hours. No significant change in the immunophenotype of peripheral blood lymphocytes was observed during this course. The patient’s quality of life was dramatically improved, with no hospitalization required and no bleeding episode observed within the 16 last months. The patient can now stand and has returned to his previous social activities. These preliminary results show that this IT treatment, performed despite a high theoretical risk of failure, resulted in this patient in a dramatic clinical improvement, even though biological criteria of success have not yet been achieved. The respective roles of the type of FVIII concentrate, and of immunosuppression remain to be assessed, as well as the cost/benefit analysis on a longer follow-up period.

A 40 year-old Caucasian patient with severe familial hemophilia A (FVIII <1%) related to an intron 22 inversion developed at the age of 2 a high-responding inhibitor. His elder brother also suffers from hemophilia A with high-responding inhibitor. Until 2000, the patient had been treated either using activated prothrombin complex concentrates (Autoplex® and Feiba®) or factor VIII (FVIII) concentrates of human (1983) and porcine origin (1992), resulting respectively in an inhibitor level rise at 360 Bethesda Units (BU) and 1800 BU. Between 2000 and 2003, the patient received exclusively recombinant activated Factor VII (NovoSeven®), and his inhibitor levels stabilized at a plateau of 15–20 BU. Between 2000 and 2003, several life or function threatening bleeding episodes occurred, such as hematomas of the iliopsoas muscles, spinal cord hematoma with transient paraplegia. Furthermore, due to hemarthroses the patient was confined to a wheelchair. Given the major impact of the inhibitor on the patient's functional prognosis, life expectancy and quality of life, immune tolerance (IT) treatment was initiated, despite the high risk of failure (initiation 36 years after inhibitor onset, historical peak titer at 1800 BU, persistence of a plateau of 15–20 BU despite the absence of any stimulation with FVIII within the 3 last years). It started with an immunosuppressive drug, mycofenolate mofetil (Cellcept®) first given in may 2003 (no effect alone on inhibitor titer) and then in November 2003, infusions of a FVIII concentrate rich in von Willebrand factor, Factane® (LFB, Les Ulis, France) using 12,000 IU/day (150 IU/kg) of FVIII. The inhibitor peaked at 520 BU on D19 and was 0.5 BU by May 2004. Thus, the FVIII dosage was progressively reduced to 7000 IU/day. In July 2005, 24 hours after a 7000 IU FVIII infusion, inhibitor level was 0.7 BU, the residual FVIII level was 0.04IU/ml with a recovery of FVIIIc of 1.37%/IU/kg infused and a half-life of 4.9 hours. No significant change in the immunophenotype of peripheral blood lymphocytes was observed during this course. The patient's quality of life was dramatically improved, with no hospitalization required and no bleeding episode observed within the 16 last months. The patient can now stand and has returned to his previous social activities.