Acquired Haemophilia A in Association with Influenza A and Urinary Tract Infection

Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by an autoantibody against any circulating coagulation factor, especially factor VIII (FVIII). The lack of awareness of this condition suggests that diagnosis is a challenge and usually delayed, which leads to suboptimal treatment. Consequently, early diagnosis is mandatory to prevent potentially life-threatening bleeding complications. We present the case of an 85-year-old woman admitted to hospital with symptoms of respiratory infection who 12 hours later developed haematuria which required transfusion. Laboratory assays showed an isolated prolonged aPTT, a moderately reduced FVIII and a high inhibitor titre. Influenza A and Escherichia coli were also identified. Antivirals, antibiotics, immunosuppressive drugs and haemostatic agents were started. Two weeks later, the inhibitor was not detected, and bleeding and symptoms of infection had resolved. Immunosuppressive drugs were stopped on day 45 and there has been no recurrence since then. To date, no FVIII inhibitors have been reported in concomitant infection with influenza A and urinary E. coli. The identification of conditions potentially associated with AHA is essential to achieve complete remission.

Case Series: Outcome and Cost Analysis of Rituximab Versus Non-Targeted Immunosuppression As First Line Inhibitor Eradication in Acquired Hemophilia a

Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder where autoantibodies interfere with factor VIII activity. AHA causes severe bleeding in 90% of affected individuals and carries a high mortality rate (8-22%). The initial factor level and inhibitor titre do not correspond to bleeding severity, and the risk of severe and fatal hemorrhage persists until the inhibitor has been eradicated. Therefore, treatment must concurrently address bleeding (with hemostatic and bypassing agents) and inhibitor eradication. Immunosuppressive therapy (IST) aims to normalize factor VIII levels by achieving the latter. With a median age of 78 years at diagnosis, AHA patients typically have more comorbidities, lower reserve, and are more susceptible to adverse events secondary to IST. In 2015, local availability of Rituximab improved via the Short Term Exceptional Drug Therapy program, allowing upfront Rituximab treatment for AHA. Prior to 2015, standard IST was steroids and cyclophosphamide as published randomized control trials comparing IST regimens are lacking. The purpose of this study was to compare Rituximab (R) to non-Rituximab (non-R) IST. Primary outcomes were time to inhibitor eradication, number of infections, and number of bleeding events. Secondary outcomes included number of hospital and emergency department (ED) admissions, mortality and relapse rate, and cost analysis. Methods A retrospective chart review was performed on all AHA patients diagnosed and treated at the Southern Alberta Rare Blood & Bleeding Disorders Comprehensive Care Clinic (SARBBDC). Data was extracted from electronic and paper medical records from the time of diagnosis to the time of death, or December 2018, whichever occurred first. Descriptive statistics were used to summarize relevant demographics and outcomes. Mann-Whitney and t-tests were used to compare groups. Kaplan Meier curves and log-rank test was used for time to inhibitor eradication. Pricing for cost analysis was obtained from the local hospital billing office, Canadian Blood Services, and the Alberta Health Services Provincial Drug Formulary (current as of April 1, 2019). Results Between 1998 and 2018, 17 AHA patients were treated at the SAARBBDC. Ten (59%) were female and seven (41%) were male. In seven (41%) of the cases, there was an underlying cause: three related to autoimmune disease, three to malignancy, and one to pregnancy. All patients received prednisone as a part of initial IST. Seven patients received R IST and 10 received non-R. Table 1 describes IST regimens and patient characteristics. The average PTT and inhibitor titre at diagnosis were greater in the R group (p=0.006, p=0.02). There were no other statistically significant differences between the groups. Median time to inhibitor eradication was greater in the R group but was not statistically significant (Figure 1, p=0.69). There were more ED visits and infections per patient in the non-R group, although not statistically significant. There were more bleeding events per patient in the R group, but the cost of bleeding treatment per patient was greater in the non-R group. Overall, there were no deaths secondary to bleeding. Mortality rate was greater in the non-R group (10% v 0%). Relapse rate was greater in the R group (14% v 10%). There was a significantly different cost for IST per kilogram between non-R and R-groups ($23.20/kg v $167.71/kg, p=0.004); no significant difference in cost for bleeding treatment per kilogram ($1479/kg v $1406/kg, p=0.41). The overall average cost per patient was greater in the non-R group despite a significantly greater cost for IST in the R group. This was mainly driven by the cost of bleeding treatment. Conclusion Overall, median time to inhibitor eradication and number of bleeding events were greater in the R group. However, the number of infections, emergency department visits, and mortality rate was greater in the non-R group despite a younger median age, suggesting the toxicity of the IST may be clinically significant. Although the cost of Rituximab is significant, there is a $13,000 cost savings on average for the treatment of an AHA patient with Rituximab-containing IST. This evidence can be used to guide clinical decision making at the local level and has the potential to reduce overall burden on our health care system. Disclosures No relevant conflicts of interest to declare.

Immune Tolerance Induction (ITI) in Paediatric and Adult Patients with Haemophilia a (HA) and High-Titre (HT) Factor VIII (FVIII) Inhibitor - Real Life Data

Introduction: In Poland, the principles for the management of rare bleeding disorders as well as financing of medication are regulated by the National Program for the Management of Haemophilia and Related Bleeding Disorders. One objective of the Program for 2012-2018 was to include the financing of ITI for all haemophilia patients with inhibitor. The qualification for ITI was performed by a physician from a Haemophilia Treatment Centre (HTC). Goal: the aim of the study is/was prospective assessment of the efficacy of ITI in real life setting. Patients and Methods: The study comprised 30 patients with severe and one with moderate HA and HT FVIII inhibitors. Factor VIII activity (FVIII:C) was measured by one-stage clotting assay and Factor VIII inhibitors by a modified Nijmegen-Bethesda assay and expressed in Bethesda Units/ml (BU/ml). Cut-off level for positive inhibitor was ≥0.5BU/ml. The following data was collected: historical peak inhibitor titre (HPT), pre-ITI titre (measured 1 month prior to ITI), peak titre recorded during the course of ITI, time between inhibitor detection and ITI start, and ITI duration. During ITI course blood samples were collected every 4 weeks. Treatment regimen with dosing and type of FVIII concentrate was at the discretion of the physician in each HTC. ITI success was defined as inhibitor titre below 0.5 BU/ml with FVIII half-life ≥6h and FVIII recovery ≥66% of normal. Partial response to ITI was defined as clinical response to FVIII therapy with no anamnestic response despite the presence of FVIII inhibitor or FVIII half-life <6h and FVIII recovery <66% of normal. Results: 31 patients with HA and inhibitor were divided into two groups: Group 1 comprised 12 adults with severe HA, median age 36 years (mean 40.1±15.1 and Group 2 included 19 boys, (<18 years) (18 with severe, one with moderate HA), median age 8 years (mean 8.1±4.3) The median (mean) duration time between inhibitor detection and ITI start was 108 months (102±91) in Group 1 and 10 months (9±10) in Group 2. The median (mean) HPT before ITI was 68 BU/ml (156±193) and 50 BU/ml (126±242) in Group 1 and 2, respectively. ITI is still ongoing in one patient (Group 1) and in 3 boys (Group 2); these 4 patients were excluded from outcome analysis. Two adult patients (16,6%) of Group 1 and 2 boys (10,5%) of group 2 discontinued ITI therapy for a variety of reasons such as death (one patient), poor compliance or loss to follow-up; those patients were however included in the outcome analysis. The median (mean) duration of ITI was 24 months (30.8±31.7) (1-120) in Group 1 and 28 months (33.4±21.4) (6-84) in Group 2. The median (mean) peak titre during ITI was 40 BU/ml (225.7±185.7) in Group 1 and 85 (160±171.7) in Group 2. Immune tolerance to FVIII (success) was achieved in 3/11 adult (27.3%) and in 6/16 paediatric patients (37.5%). Median HPT, median time between inhibitor detection and ITI start, median peak inhibitor titre during ITI and median duration of ITI in patients who achieved immune tolerance were 380 BU/ml, 120 months, 8 BU/ml, 33 months in Group 1 and 22.5 BU/ml, 9.5 months, 205 BU/ml, 25 months in Group 2, respectively. No partial response to ITI was observed in our patients. The most common initial ITI regimen in both groups was 100 IU/kg/d of FVIII (50 - 200 IU/kg/d). In 28/31 (90.3%) patients only plasma derived FVIII concentrates were used which contained various amounts of von Willebrand factor. In two patients recombinant FVIII was administered. Recombinant, plasma derived and EHL FVIII concentrates were used in the case of one boy. In two patients immunosuppressive therapy (prednisone or rituximab) was concomitantly applied. Conclusions: it is our belief that the presented real-life data reflects i) the challenge of ITI therapy in clinical practice and ii) wide variety of approaches to ITI strategy in individual haemophilia treatment centres. Disclosures Windyga: Octapharma: Honoraria, Research Funding; Rigel Pharmaceuticals: Honoraria, Research Funding; Ferring Pharmaceuticals: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Werfen: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Baxalta/Shire (a Takeda company): Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Siemens: Honoraria, Research Funding; Sobi: Honoraria, Research Funding.

Immune Tolerance Induction with Simoctocog Alfa (Nuwiq®) in Six Patients with Severe Haemophilia a and FVIII Inhibitors

Introduction and Objective: Inhibitors to coagulation factor VIII (FVIII) are the most serious complication of haemophilia A treatment. Previously untreated patients (PUPs) are at the greatest risk of inhibitors, which generally occur within the first 20 exposure days (ED) to FVIII. Immune tolerance induction (ITI) is the only clinically proven strategy for eradication of inhibitors. We present a case series of six PUPs with severe haemophilia A and inhibitors who underwent ITI with simoctocog alfa (Nuwiq®), a 4th generation human cell-line-derived recombinant FVIII approved for treatment of haemophilia A. Materials and Methods: Six male PUPs with severe haemophilia A who developed FVIII inhibitors after treatment with simoctocog alfa were started on ITI with simoctocog alfa. Primarily, we assessed the success of simoctocog alfa in patients with inhibitors. Success of ITI was determined based on undetectable inhibitor titre (< 0.6 BU/ml), FVIII recovery ≥ 66% and half-life ≥ 6 hours. Secondary objectives were to assess bleeding rate, tolerability and safety in patients with inhibitors treated with simoctocog alfa ITI. Results: The age of the patients at the start of ITI ranged from 8 to 186 months. Four of the patients were Caucasian, and two were African. All patients had a F8 mutation associated with high risk of ITI failure and two patients had an additional risk factor for ITI failure. The number of EDs prior to inhibitor development ranged from 9 to 33, and the peak inhibitor titre ranged from 0.9 to 114 BU. For ITI, five patients were treated with 100 IU/kg simoctocog alfa daily, and one with 90 IU/kg every other day. One patient achieved complete tolerisation and is now on prophylaxis at normal doses, having achieved an undetectable inhibitor titre after 9 months. This was despite an inhibitor titre ≥ 10 BU/mL at ITI start, which is considered a poor prognosis factor for ITI success. Three other patients achieved an undetectable inhibitor titre after 1, 6 and 18 months of ITI, and FVIII recovery has normalised but half-life remains short and they are on weaning doses as the half-life extends. One patient discontinued ITI with simoctocog alfa after 15 months due to an increasing inhibitor level. This patient was 15 years old at ITI start, and older age is associated with poor ITI outcome. Additionally, his haemophilia A was untreated for 15 years, during which time he developed severe arthropathy. One patient, who started ITI 3 months ago, has an ongoing inhibitor titre and continues on ITI with simoctocog alfa. Conclusions: In a case series of six patients treated with simoctocog alfa for ITI, who all had poor prognosis factors for ITI success, four patients (67%) to date have achieved an undetectable inhibitor titre. These data suggest that ITI with simoctocog alfa may be an effective treatment approach in haemophilia A patients with inhibitors. Disclosures Khair: Shire, SOBI, Pfizer, Roche, Novo Nordisk, Octapharma: Speakers Bureau; shire, SOBI, Pfizer, Roche: Research Funding. Liesner:Roche: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Sobi: Speakers Bureau. Belyanskaya:Octapharma AG: Employment.

Adamts-13 Inhibitor Testing Is Often Negative on Initial Testing

Background: Thrombotic thrombocytopenic purpura (TTP) presents with microangiopathic hemolytic anemia and thrombocytopenia and is caused by severe ADAMTS13 deficiency. TTP can be the result of autoantibodies to ADAMTS13 or genetic defect in the ADAMTS13 gene. ADAMTS-13 is an enzyme that specifically cleaves unusually large von Willebrand Factor (VWF) multimers which mediate platelet thrombus formation under high shear. When ADAMTS13 is deficient, unusually large VWF multimers accumulate causing excessive platelet aggregation and thrombosis in the microvasculature. Methods: St. Michael's Hospital, Toronto is home to a large reference laboratory for special coagulation. We use a commercial ELISA Technoclone Technozym ADAMTS-13 activity assay for the determination of ADAMTS-13 activity and Technoclone Technozym ADAMTS-13 inhibitor assay to identify anti-ADAMTS-13 antibodies. We send samples to another Canadian laboratory for validation of our results as they use an in-house ELISA assay for ADAMTS13 activity and anti-ADAMTS13 antibody. Results: We performed a retrospective review of all ADAMTS13 activity tests performed by our laboratory between January 1, 2013 and June 30, 2018. The total number of tests was 466 from 203 unique patients. 24% had an ADAMTS-13 activity under 10% (N = 144) which is consistent with the diagnosis of TTP. When specimens with severe ADAMTS-13 deficiency were tested for presence of anti-ADAMTS13 antibody, 46% were negative. Four of these specimens were sent to the other laboratory and all had detectable, albeit very low titre, inhibitors. Furthermore, on repeated testing over the study period, the vast majority of patients who presented with low ADAMTS13 activity and no detectable antibody subsequently became antibody positive. Fifty-two patients remained antibody negative by our internal and send-out testing. Five of them were known to have or were subsequently diagnosed with hereditary TTP (hTTP). Only one patient continues to have negative antibody but whose clinical course is not consistent with hTTP. Conclusions: We found that a commercial ADAMTS13 (Technoclone Technozym) antibody assay is falsely negative in a substantial proportion of patients with autoimmune TTP, the majority of which likely had a low titer inhibitor, below the threshold of test detection. More sensitive assays and/or repeated testing, presumably as inhibitor titre increases during the course of the disease, may detect antibody presence in the majority of samples of patients with autoimmune TTP. This is an important finding as this could impact the types of therapies offered to patients with negative antibody screens and may also avoid unnecessary, expensive genetic testing . Disclosures No relevant conflicts of interest to declare.

Outcome of Immune Tolerance Induction Using an Extended Half-Life Clotting Factor Concentrate — Recombinant Factor VIII Fc (Eloctate™) — a Report from India

The development of inhibitors is the most serious adverse effect of replacement theray with clotting factor concentrates (CFC) in hemophilia. Its eradication is also difficult, usually requiring months of frequent exposure to high doses of the CFC - immune tolerance induction (ITI). There is limited data on use of extended half-life (EHL) CFC for ITI. A limited program of ITI was made possible in India with some of the rFVIIIFc (Eloctate™) provided through the humanitarian aid program of the World Federation of Hemophilia. This report summarizes the interim outcome of ITI in these patients treated at three centers participating in this program. ITI with rFVIIIFc was offered to patients with hemophilia A and significant inhibitors. The CFC dose used ranged from 50 IU/kg, 3x/week, to 200 IU/kg per day, depending on the weight, convenience and early response as well as availability of rFVIIIFc. All patients completing at least 10 weeks of ITI are included in this analysis. Bethesda assay was done every 2-4 weeks. Successful ITI was defined as a negative Bethesda assay with a FVIII recovery of >60%. Patients received either FEIBA or rVIIa for breakthrough bleeds. Thirty eight patients were included in this analysis. The median age at initiation of ITI was 15 years (range:2 -39). Nine (24%) patients had a family history of inhibitors. The median age at which inhibitors developed was 11 years (range:0.6 -38). Nine (24%) patients had history of surgery prior to onset of inhibitor. Ten patients (26%) had exposure to only plasma derived factors. All patients were on episodic CFC replacement therapy except two (5%) who were receiving low-dose prophylaxis prior to inhibitor development. The median exposures to FVIII was 20 (range:2-80) and duration of inhibitors prior to ITI was 2 years (range:0.1 - 20). The median highest inhibitor titre recorded prior to ITI was 19 BU (range:4-1177). Only 3 patients had their maximum inhibitor titer below 5BU. The median inhibitor titre at the time of starting ITI was 10.4 BU (range: 0.6-1177). The median peak inhibitor titer after starting ITI was 40.4 BU (range:3.5-13933). Out of the 38, 17 (45%) patients achieved a negative inhibitor status after ITI for a median duration of 23 weeks (range: 10-64). Among the 17 patients who had successful ITI, the median duration of ITI required to achieve negative inhibitor status was 20 weeks (range:10-60). Among the other 21 patients who had persistence of inhibitors, 4 were included in other clinical trials, 3 discontinued due to personal reasons while the other 14 are continuing ITI based on availability of appropriate EHL CFC. Among these patients with persistence of inhibitors, the last inhibitor titer was 6.4 BU (range:0.9-9240) after a median of 26 weeks of ITI (range:11-64). The median number of breakthrough bleeds during ITI was 1 (range:0-12), being 1 (range:0-6) among responders and 1 (range:0-12) among those with persistence of inhibitors. A comparison of the group which responded within this duration of ITI and those who did not respond is shown in the table. Older age and the peak inhibitor titer prior to ITI were the two significant variables which affected early outcome of ITI. These data show that EHL rFVIIIFc can be effective in ITI with nearly 45% of patients achieving a negative inhibitor titer within 1 year and with responses starting as early as 1 month and nearly half of them within 4 months. There was also a relatively low median annualized bleed rate during ITI. More patients need to be treated with different doses of rFVIIIFc to assess its potential in ITI and to determine the optimal protocols but the initial data is promising. Disclosures No relevant conflicts of interest to declare.

Treatment of Haemophilia a (HA) Patients with Inhibitors: Immune Tolerance Induction with a Single Factor VIII/Von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study (ObsITI)

Introduction and objectives: Development of neutralising inhibitors against factor VIII (FVIII) is one of the most serious and costly complications in the treatment of HA. An ongoing international, open-label, uncontrolled, multicentre observational study, ObsITI (ClinicalTrials.gov. NCT 02207894) started in 2005 to assess immune tolerance induction (ITI), the standard of care in patients with inhibitors. The study evaluates patient- and therapy-related variables on ITI course, outcome and morbidity in HA patients with inhibitors. ObsITI satellite studies additionally look at other factors related to tolerisation. Methods and Materials: As of February 2018, 193 patients from 20 countries undergoing ITI have been recruited in ObsITI. 152 patients completed the study and 41 are ongoing. A subgroup of more than 80 prospective patients were treated exclusively during the complete ITI course with a single plasma-derived (pd) FVIII concentrate that contains von Willebrand factor (VWF) in a VWF/FVIII ratio of 0.4 (Octapharma AG). According to the recommended Bonn protocol, low responders at ITI start received 50-100 IU FVIII kg-1 daily, or every other day; high responders received 100 IU FVIII kg-1 every 12 hours. Results: In this ongoing study, the majority of patients treated with the pdFVIII/VWF product achieved a negative inhibitor titre. ITI outcome was significantly correlated with the bleeding rate during ITI, the peak titre during ITI, the inhibitor titre at start of ITI >10 BU, and the number of poor prognosis factors. Conclusion: Treatment with this particular pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in HA patients with inhibitors and corroborates previously published success rates (77.1% complete/partial success in 48 inhibitor patients undergoing ITI with the same product). Disclosures Escuriola Ettingshausen: SOBI: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria; Roche: Honoraria; Grifols: Honoraria; Pfizer: Honoraria; LFB: Honoraria. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: 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; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Research Funding. Pavlova:Novo Nordisk: Honoraria; Octapharma: Honoraria. Oldenburg: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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: 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; 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; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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.

The prevalence of factor VIII inhibitor in patients with severe hemophilia-A and its clinical characteristics

Background Hemophilia is a hereditary blood-clotting disorderdue to factor VIII deficiency. Up to this date, the administration offactor VIII in preventing and managing bleeding has been the maintreatment. One of the complications, which may occur due to re-peated administrations of factor VIII, is the formation of factor VIIIantibody (factor VIII inhibitor).Objective To find out the prevalence of severe hemophilia-A withfactor VIII inhibitor and its clinical characteristics.Methods A cross-sectional descriptive study was performed onchildren with severe hemophilia-A at the National Hemophilia CareCentre, Cipto Mangunkusumo Hospital, Jakarta, Indonesia, in June-August 2004.Results Out of 45 children studied, 16 had factor VIII inhibitor withaverage inhibitor titre of 1.15 Bethesda units (BU) (range 0.15-15BU). Most of them (12 patients) had inhibitor titre <5 BU. Chronicarthropathy was found in 17 out of 45 (37%) children with severehemophilia-A, consisting of nine patients from positive inhibitorgroup and 8 patients from negative inhibitor group. Thirty-ninepatients (86%) used an on-demand treatment pattern, among whom15 had positive inhibitor. Among patients receiving prophylactictreatment pattern, only one had positive inhibitor. There were 39patients (86%) treated using cryoprecipitate, among whom factorVIII inhibitor was found in 12, while among those treated with fac-tor VIII concentrate, the inhibitor was positive in 4/6. The averageamount of factor VIII transfused in positive and negative factor VIIIinhibitor groups was similar.Conclusion The prevalence of factor VIII inhibitor in severe he-mophilia-A patients was 35%. Chronic arthropathy occurred moreoften in patients with positive factor VIII inhibitor. Factor VIII inhibi-tor was found more frequently in patients with an on-demand treat-ment pattern and in those using factor VIII concentrate

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

SummaryThere 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.