Haematologica 2000;85:supplement to no. 10 - Supplements ...

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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 3 PUPs with hemophilia A (defined here as having baseline FVIII values of < 2%), but some with moderate (2-5% baseline FVIII) and mild (> 5% FVIII) hemophilia A as well. 5 Patients were enrolled between January, 1989 and April, 1992; 101 patients were entered, treated and evaluable. Sixty-four of the 101 had severe hemophilia A. Each patient received the study product (Kogenate ® ) only, for all bleeding episodes and/or prophylaxis. Following each PUPs first treatment with Kogenate ® , inhibitor assays were done every 3 months (or sooner, if inhibitor development was suspected clinically). 5 The study cohort included 92 Caucasians and “others”, and 9 Blacks (of African descent). Thus, 19 of 64 (29.7%) severe hemophilia A PUPs developed inhibitors. During the course of the study, 21 of 101 (20.8%) patients developed inhibitors after a median of 9 exposure days (ED) to rFVIII (range, 3-51ED). Nineteen of the 21 inhibitors developed in severely affected patients, and 2 in moderately affected patients. Ten of the 19 were high titer (> 10 Bethesda Units [BU]) and 9 low titer < 10 BU). Eight of the inhibitors were transient, disappearing while the patient received episodic (on demand, or, as necessary) treatment with Kogenate ® . 6 During the study period, 8 inhibitor patients were started on immune tolerance (ITI) regimens with Kogenate ® ‚ alone, and five were successfully tolerized while two others remained on ITI at the conclusion of the Kogenate ® ‚ PUP trial. At that time, 8 patients (8 of 101, or 7.9%) still had an inhibitor, 6 of which were high titer and 2 low titer. Of 9 Black children in this cohort, 4 developed inhibitors, all of which were high titer. The Recombinate ® PUP Trial The PUP trial with Baxter’s Recombinate ® ‚ began in July, 1990; patient enrollment was closed in March, 1992, and the last patient received his first treatment with Recombinate in August, 1993. Although the trial design was quite similar to that of the Kogenate ® trial, the Recombinate ® trial enrolled only severely affected PUPs. 7,8 Of 72 treated and evaluable PUPS, 22 (31%) developed inhibitors after a median number of 10 ED. Nine were high (> 5 BU) and 13 low titer (≤ 5 BU); 12 were transient, having disappeared on episodic treatment (7 patients) or while receiving regular (e.g. twice weekly) infusions of Recombinate ® (5 patients). 9 In this cohort, 6 patients with high responding inhibitors were started on ITI with Recombinate ® alone, and only one of these was tolerized by study exit. 9 Nine of the 72 Recombinate ® PUPs were Black children; 5 of 9 (55%) developed inhibitors, all of which were low titer. In contrast, 17 of 63 (27.4%) Caucasians and “others” developed inhibitors. By 1998, the prevalence of inhibitors was 14% (10 of 72). 9 The French PUP Study with rFVIII A French study with rFVIII was conducted from 1993 to 1996; 52 severely affected PUPs (< 1% FVIII) were enrolled, and evaluated. Fifty received Kogenate ® ‚ exclusively, while 2 received Recombinate ® exclusively. 15/52 (28.8%) developed inhibitors, 5 of which were low titer (< 10 BU) and 10 high titer (≥ 10 BU). Five of the inhibitors were transient. Eleven of 44 Caucasian children developed inhibitors, while 2 of 6 Arabic and 2 of 3 Black children did. Nine of 20 (45%) children who had the inversion mutation developed inhibitors, while only 18% of those who were negative for the inversion mutation did so. 10 Prospective clinical trials in PUPs with “second generation” rFVIII concentrates The PUP Trial with B-Domain Deleted rFVIII (ReFacto ® ) A multicenter, multinational prospective trial with rFVIII SQ (ReFacto ® ) in PUPs began in 1994; severe hemophilia A PUPs were enrolled between October, 1994 and 1996. In this trial, 101 PUPs were enrolled, treated and evaluable. 11 This product differs from Kogenate ® and Recombinate ® not only in that the rFVIII lacks the B domain, but also in the fact that no human serum albumin is added as a stabilizer (additionally, while chromogenic and two-stage FVIII assays give expected recovery values in recipients, one-stage assays give roughly half the expected values). After 4 study years, the percentage of patients having developed inhibitors is 30% (30 of 101 severely affected PUPs). In 11 of the inhibitors patients, the peak inhibitor titer was ≥ 10 BU, while in 5 it was 5-10 BU, and in 14 it was < 5 BU. 12 Fifteen of 17 patients who were started on an ITI regimen with rFVIII SQ had a reduction in inhibitor titer, with 9 of the 15 achieving a negative Bethesda assay by the time of the interim data analysis. 12 In 6 additional patients treated “on demand”, the inhibitor disappeared spontaneously. Fifteen PUPs still have an inhibitor (9 of the 15 were originally > 10 BU, while the other 6 were < 5 BU). Thus, the current prevalence of inhibitors in the cohort is 15% (15/101), with or without immune tolerance. 12 The median number of exposure days to inhibitor detection is 12 (range 3-49 ED) in the entire group of 30 inhibitor patients. It was 9 Haematologica vol. 85(supplement to n. 10):October 2000
4 J.M. Lusher (range 1-34) for patients with high titer (≥ 5 BU) inhibitors. In all patients, the median number of ED at the time of interim data analysis was 55. 12 The PUP (and, Minimally Treated Patient) Trial with a Second Generation rFVIII Concentrate Formulated with Sucrose Rather than Albumin (Kogenate ® FS) From October, 1997 until April 30, 1999, 62 infants and young children with severe hemophilia A (< 2% FVIII) were enrolled in a prospective, multicenter, multinational safety and efficacy study of a second generation rFVIII concentrate which is formulated with sucrose rather than human serum albumin (rFVIII-FS; Kogenate ® FS). The 62 study subjects included 38 PUPs and 24 minimally treated patients (MTPs) with < 4 ED to rFVIII (one MTP received a plasma-derived FVIII concentrate, while the other 23 MTPs had received only rFVIII). All had negative inhibitor assays (Nijmegen modification 13 of the Bethesda assay) at study entry. Once on study, all patients received only rFVIII-FS, for treatment of bleeding or for prophylaxis. Inhibitor assays were performed every 3-4 ED for the first 20 ED or every 3 months (whichever came first); every 10 ED from 21-50 ED or every 3 months (whichever came first); and every 3 months thereafter. As of August, 1999, 61 of 62 study subjects had been treated with rFVIII-FS, and 8 had developed an inhibitor after 2-15 ED (median 7 ED). Among 5 American patients who developed inhibitors, 2 were African-American children (of 5 African-Americans in the study). Of the 8 inhibitor patients, 5 (all American patients) were high titer (16, 23, 109, 249, and 271 BU) while 3 (all European) were low titer (1.25, 1.9, and 4.0 BU). However, many of the subjects in this cohort are still at risk for inhibitor development, having had relatively few ED (29 still had < 10 ED). 14 Prospective clinical trials with rFVIII preparations in previously treated patients Prospective clinical trials have been conducted in previously treated patients (PTPs) with the two full-length rFVIII preparations (Kogenate ® and Recombinate ® ), and with the B-domain deleted rFVIII (ReFacto ® ). 15-18 In the PTP trial with Kogenate ® , 58 patients received Kogenate ® exclusively in an international, multicenter, prospective study of more than 5 years duration. Fifty-four of the 58 subjects had severe hemophilia A (
Page 1 and 2: Haematologica established in 1920 e
Page 3 and 4: Acknowledgments We wish to thank th
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Page 9 and 10: 6 J.M. Lusher ALEDORT: I’d just l
Page 11 and 12: 8 J. Oldenburg et al. Tuddenham et
Page 13 and 14: 10 J. Oldenburg et al. Table 4. Mut
Page 15 and 16: 12 J. Oldenburg et al. reactions ac
Page 17 and 18: 14 J. Oldenburg et al. Dr. Schwaab
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60 C.M. Kessler in eradicating allo
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66 L. Nemes et al. Figure 1. A gian
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II Immune Tolerance and the Treatme
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