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Haematologica Journal of Hematology volume 85 – supplement to number 10 – October 2000 Haematologica 2000; 85(suppl. to n.10) Foreword Inhibitor appearance in haemophilia is considered by far the severest problem of hemophilia treatment, being associated with increased morbidity if not mortality. The presence of an inhibitor, especially if high-titre, leads to a clinical setting which is comparable to that of the early years of haemophilia treatment where bleedings were difficult to treat and arthropathy was rapidly progressing towards disability. This issue of Haematologica, a fastly growing international journal of haematology, contains selected papers from the III Workshop on Immune Tolerance which took place in Palermo, Italy, October 1999. The discussion developed during the meeting has been included, which has involved a major editorial effort. All things considered, this volume contains a great deal of information valuable for the researchers and the treaters. However, in the recent years, new drugs and treatment modalities have been proposed which modified this otherwise gloom scenario. In addition, the scientific knowledge on the matter has grown in a tumultuous way and important fall out concerning the management of patients with inhibitors to FVIII are foreseen in the forthcoming years. Among the many issues of interest, we are understanding more about the humoral and cellular mechanisms of inhibitor formation and some of the processes underlying the return to a tolerant status towards FVIII. Guglielmo Mariani Hans-Hermann Brackmann Haematologica vol. 85(supplement to n. 10):October 2000
Haematologica 2000; 85(suppl. to n.10) p. 2-6 Epidemiology and Treatment of FVIII and IX inhibitors Factor VIII inhibitors with recombinant products: prospective clinical trials JEANNE M. LUSHER Children’s Hospital of Michigan, and Wayne State University School of Medicine Detroit, Michigan, U.S.A. Abstract Background and Objectives. During the late 1980s, short-term hepatitis safety trials with certain new high purity, virally attenuated plasma derived factor VIII (FVIII) concentrates showed a higher than anticipated percentage of inhibitors in previously untreated patients (PUPs). Thus, the design of prelicensure clinical trials with each of the recombinant (r) FVIII products included prospective evaluations for inhibitors at well-defined time points, to see whether treatment with rFVIII resulted in a higher incidence of inhibitors. Design and Methods. Each of several prospective clinical trials with rFVIII preparations is described and analyzed in terms of inhibitor development, patient demographics, and current prevalence of inhibitors in the cohort. Results. In prospective trials with rFVIII preparations (both full length and B domain deleted rFVIII), the percentage of PUPs with severe hemophilia A who developed FVIII inhibitors has varied between 28.3 and 30.6%. Many of the inhibitors have been transient, disappearing while the patient was receiving episodic (on demand) treatment with rFVIII, while others have responded to immune tolerance induction regimens with rFVIII alone. However, many other have persisted. Genetic influences (underlying gene defect and race) were shown to play a role in inhibitor development. In contrast to the experience in the PUPs, in trials with rFVIII preparations in previously treated patients (PTPs), only 0-1 subject per trial developed an inhibitor. Interpretation and Conclusions. While the percentage of PUPs developing inhibitors in each of the prospective clinical trials with rFVIII preparations appears high, published data from similarly conducted studies with plasma-derived FVIII products show very similar results. Additionally, only an occasional PTP on rFVIII developed an inhibitor. Thus, none of the rFVIII preparations studied to date appears to be more immunogenic than plasmaderived FVIII. ©2000, Ferrata Storti Foundation Key words: recombinant (r) FVIII, B domain deleted rFVIII, recommendations of the FVIII/FIX subcommittee, transient inhibitors, genetic influences Correspondence: Jeanne M. Lusher, M.D., Division of Hematology- Oncology, Children’s Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, MI 48201 U.S.A. Telephone: 313-745-5515 – Fax: 313-745-5237 – E-mail: jlusher@med.wayne.edu With the introduction of high purity, virally attenuated plasma derived factor (F) VIII concentrates in the late 1980s, there was some concern that such manipulations might render FVIII more immunogenic. Thus, the hepatitis safety trials conducted in previously untreated patients (PUPs) with these new products included inhibitor assays. While these short-term trials were aimed at assessing hepatitis safety 1 and usually included only a few inhibitor assays done at 6 month intervals, a surprisingly high percentage of PUPs in one prospective study developed inhibitors early in the trial. 2,3 Reports of higher than expected inhibitor development in other small pediatric patient cohorts 4 also raised concerns. Thus when recombinant (r) FVIII products became available for human use in 1987 and 1988, the design of pre-licensure clinical trials included inhibitor assays every 3 months (or sooner if an inhibitor was suspected clinically). Design and Methods We looked at inhibitor development in the prospective clinical trials with each of the currently available rFVIII preparations (Bayer’s Kogenate ® , Baxter’s Recombinate ® , Genetics Institute’s ReFacto ® , and Bayer’s Kogenate ® FS). The trials with the first two of these products have been completed, while the ReFacto‚ and Kogenate ® FS are closed to patient entry but are still accruing data. Demographics, and genetic factors (when available) are described for each cohort, and for those who did or did not develop inhibitors. The number of high and low titer inhibitors, transient inhibitors, and current inhibitor prevalence in each cohort was also looked at. Prospective clinical trials in previously untreated patients with “first generation” full-length rFVIII concentrates The Kogenate ® PUP Trial The first rFVIII trial in previously untreated patients (PUPs) began in January, 1989, with Bayer’s Kogenate ® . This multinational, multicenter trial enrolled not only severely affected Haematologica vol. 85(supplement to n. 10):October 2000
Page 1 and 2: Haematologica established in 1920 e
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II Immune Tolerance and the Treatme
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