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• W2114841273 abstract "It was with great interest that we read Mannucci's commentary on the need for randomized trials in hemophilia [1Mannucci P.M. Need for randomized trials in hemophilia.J Thromb Haemost. 2006; 4: 501-2Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. The international immune tolerance induction (I‐ITI) study, initiated in July 2002, is the only prospective randomized multicenter trial of immune tolerance therapy (ITI). A previously published retrospective meta‐analysis of the International [2Mariani G. Scheibel E. Nogao T. Kasper C.K. Ewing N.P. Mauser‐Bunschoten E. Ghirardini A. Bellocco R. Brackman H.H. Immunetolerance as treatment of alloantibodies to factor VIII in hemophilia. The International Registry of Immunetolerance Protocols.Semin Hematol. 1994; 31: 62-4PubMed Google Scholar] and North American [3DiMichele D.M. Kroner B. and the North American Immune Tolerance Study GroupThe North American Immune Tolerance Registry: practices, outcomes, outcome predictors.Thromb Haemost. 2002; 87: 52-7Crossref PubMed Google Scholar] ITI registries suggested that outcome was independent of dosing regimen in good‐risk high titer inhibitor patients with severe hemophilia A (sHA) [historical peak titer ≥ 5 Bethesda Units (BU) mL−1 and ≤ 200 BU mL−1; and starting titer of < 10 BU mL−1] [4Kroner B.L. Comparison of the International Immune Tolerance Registry and the North American Immune Tolerance Registry.Vox Sang. 1999; 77: 33-7Crossref PubMed Google Scholar]. The I‐ITI trial was designed to test this hypothesis by randomizing 150 good‐risk pediatric sHA patients aged < 8 years with inhibitors present for < 12 months (criterion recently extended to < 24 months) to receive either high‐ (200 IU kg−1 day−1) or low‐dose (50 IU kg−1 thrice weekly) factor (F) VIII. Success is defined by a negative inhibitor titer [< 0.6 BU mL−1; < 0.3 BU mL−1 (Nijmegen method)], and normal FVIII recovery (≥ 66% of expected) and half‐life (≥ 6 h). Subjects use the FVIII product of their physician's choice. Randomization is computerized and uses the method of minimization to balance treatment arms for product type and starting inhibitor titer. Data are collected electronically, analyzed centrally, and adjudicated prospectively by an independent Data Safety Monitoring Committee (DSMC). The randomization code will not be broken until the study concludes. However, with more than a third of the targeted recruitment completed as of January 2006, we wish to share some interesting preliminary observations with the international hemophilia community. Eighty centers in 21 countries from North America, Western Europe, Oceana and Asia have recruited 54 subjects into the study to date. Forty‐five of these subjects, whose titers have declined to < 10 BU, have been randomized so far at a median age of 25 months (range: 13–80). These subjects have required a median of 5 months (range: 0–12) from diagnosis for their titers to decline to < 10 BU mL−1. Importantly, the early concern that allowing for this decline in inhibitor titer would result in a considerable delay in ITI initiation has not yet been warranted. So far, 36 subjects are undergoing or have undergone tolerance with recombinant FVIII; eight are receiving plasma‐derived product. Median peak historical and starting titers for the entire randomized cohort are currently 21.0 (range: 7–175) and 5.0 (range: 0.6–9.4) BU mL−1, respectively. Notably, recruits have so far come from the whole range of inhibitor titers prescribed by the protocol. The median peak titer on ITI at this time in the study is 3.1 (0.6–2093) BU mL−1. The randomized group has been on ITI for a median of 20.5 months (range: 1–33). Twenty‐eight (62%) have achieved a negative titer after a median of 6 months (range: 1–18) on therapy. Twenty‐three (50%) now have a normal FVIII recovery following a median of 7.5 months of ITI (range: 2–25). To date, 14 (31%) have become tolerant after a median of 12 months (range: 5–25) of treatment and have a median FVIII half‐life of 7 h (range: 6.5–9.9). Although the two treatment arms cannot yet be compared, the median time to the achievement of each incremental milestone of ITI success for the whole cohort is similar to the data published on patients treated with high‐dose ITI [5Mariani G. Kroner B. Immune tolerance in hemophilia with factor VIII inhibitors: predictors of success.Haematologica. 2001; 86: 1186-993PubMed Google Scholar, 6Brackmann H.H. Oldenberg J. Schwaab R. Immune tolerance for the treatment of FVIII inhibitors‐twenty years of the Bonn protocol.Vox Sang. 1996; 70: 30-5Crossref PubMed Google Scholar, 7Freiburghaus C. Berntorp E. Ekman M. Gunnarsson M. Kjellberg B.M. Nilsson I.M. Tolerance induction using the Malmo treatment model 1982–1995.Haemophilia. 1999; 1: 32-9Crossref Scopus (118) Google Scholar, 8Smith M.P. Spence K.J. Waters E.L. Beresford‐Webb R. Mitchell M.J. Cuttler J. Alhaq A. Brown S.A. Savidge G.F. Immune tolerance therapy for hemophilia A patients with acquired factor VIII alloantibodies: comprehensive analysis of experience at a single institution.Thromb Haemost. 1999; 81: 35-8Crossref PubMed Google Scholar, 9Rocino A. Papa M.L. Salerno E. Capasso F. Miraglia E. DeBiasi R. Immune tolerance induction in hemophilia A patients with high‐responding inhibitors to factor VIII: experience at a single institution.Haemophilia. 2001; 7: 33-8Crossref PubMed Scopus (0) Google Scholar]. To date, seven of 45 subjects (15%) have failed ITI according to study criteria. Furthermore, two of 14 tolerized subjects relapsed at 1 and 9 months on prophylaxis after achieving ITI success by study criteria. In this time period, 102 serious adverse events (SAEs) have been reported, 85% of which were determined by the DSMC to be unrelated to the study or product. All were hospitalizations, for reasons that included 29 bleeding episodes in 14 subjects, and 44 catheter infections in 13 subjects with central venous access catheters (CVADs). In all, 36 subjects have so far had 52 CVADs placed (30 Portacaths, 14 Broviac/Hickman catheters and eight peripherally placed central lines). CVADs were placed in six subjects specifically for ITI, in 28 for general venous access and in two for unstated reasons. A median of two (range: 1–5) CVADs were inserted per subject requiring access. Thirteen of 36 subjects (36%) developed ≥ 1 CVAD infection after a median of 102 catheter days (range: 15–682). Infected subjects have had a median of three (range: 1–12) such events. So far, 27/44 gram‐positive, 15/44 gram‐negative and 2/44 fungal infections have been reported. Infections were significantly more common in patients with Broviac/Hickman catheters than in those with Portacaths. Five of six (83%) patients with Broviac/Hickman lines at the start of ITI developed an initial infection compared with seven of 26 (27%) patients with Portacaths. This difference is statistically significant (P = 0.005, Peto log‐rank test; Fig. 1). The median ages at randomization for ‘infected’ (at least one infection observed during the study period) and ‘uninfected’ (no infection observed so far) subjects were 19 and 24 months, respectively (P = ns). Importantly, of the 11 tolerant patients so far, only three (27%) had suffered a CVAD infection prior to tolerization. Furthermore, of the 22 patients with catheters who have achieved a negative Bethesda titer, to date, only five (23%) had a prior infection. The median time to a negative titer was also 14 months in this subgroup compared with 7.5 months in the 17 subjects (77%) who had remained infection‐free. Finally, of the 13 patients who had ≥ 1 CVAD infection, five (38%) have failed ITI. This overall success rate is lower, the failure rate higher, and response to ITI much slower compared with the uninfected subgroup. These preliminary findings suggest that catheter‐related infection may have an adverse effect on ITI outcome. Because one of the original specific aims of this trial was to study the specific impact of catheter‐related morbidity on ITI outcome, these data will continue to be very actively monitored. However, these results are too preliminary for specific recommendations regarding the type of catheter placed for ITI. In summary, this investigator‐driven prospective randomized ITI trial has broad international support from a committed group of participants, steadily continues to accrue study subjects, and has begun to yield some important and interesting information about ITI outcome in general and the impact of catheter‐related infection in particular. Furthermore, satellite studies have been initiated to study both the impact of genotype of ITI outcome and the immunology of tolerance induction. The international hemophilia community has been slow to embrace the multicenter, prospective, randomized interventional trial, even though it provides the best way to achieve an evidence‐based standard of care for a rare disease. Nonetheless, we remain committed to this investigative model and to the completion of this trial. The authors state that they have no conflict of interests. We are grateful for the support given by our expanding group of investigators, our DMSC chaired by L. Aledort, our group of industry sponsors, and our committed trial‐coordinating staff. To date, our industry sponsers include ZLB Behring, Wyeth, Bayer Healthcare and Baxter Bioscience." @default.
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• W2114841273 title "The international immune tolerance study: a multicenter prospective randomized trial in progress" @default.
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