Immune Tolerance Induction in 28 Children with Hemophilia Awith Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1046-1046
Author(s):  
Michael U. Callaghan ◽  
Indira Warrier ◽  
Madhvi Rajpurkar ◽  
Jeanne Lusher
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Hemophilia B ◽  
Recurrent Infections ◽  
Severe Hemophilia ◽  
Central Venous ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
Peak Titer

Abstract Aim: To study the characteristics, treatment, and outcome of patients with hemophilia with inhibitors who have undergone immune tolerance induction (ITI) at the Children’s Hospital of Michigan over the past 14 years. Methods: In compliance with local IRB regulations, patient charts and laboratory databases were reviewed and salient data extracted. 28 boys underwent 29 attempts at immune tolerance induction. Results: Hemophilia A 26 boys with severe hemophilia A with inhibitors underwent 27 trials of ITI. In this cohort of 26 patients the average age at which patients developed an inhibitor was 22 months and the average age at start of ITI was 5 years 4 months (range 2 months to 17 years 5 months). The average number of exposure days prior to inhibitor development was 10 (1–47). The average time between development of an inhibitor and initiation of ITI was 43 months, with no difference between those who successfully completed ITI and those who did not. Six patients had low titer inhibitors (0.8–6.5 BU) and successfully completed ITI using a modified low dose ITI regimen of factor infusions 3–7 times per week. 20 of the patients with high titer inhibitors (6.4–1280 BU) were treated with daily infusions of 50–200 units/kg/d of factor VIII (FVIII) products. For ITI, 4 patients received high purity plasma derived FVIII (PD-FVIII) and 21 received recombinant FVIII (rFVIII) and one received both. In patients who became tolerized to FVIII, the average time to achieve an inhibitor titer of 0 Bethesda Units (BU) was 211 days. In those who were unable to achieve tolerance, the average length of the trial was 263 days. 21 of the ITI trials employed a central venous catheter and in 5 patients ITI was stopped after removal of the line because of recurrent infections. 14 boys received FEIBA, rFVIIa, or porcine FVIII for bleeding episodes during ITI; 8 of them failed ITI and one is still on therapy. Seven trials of ITI were in Caucasian patients (26 %), 17 in African American (AA) (63 %), and 3 in Middle Eastern patients (11 %). 19 patients achieved complete tolerance (73 %), 6 patients failed (23 %), one failed twice, and one patient continues on therapy. All but 2 patients who successfully completed ITI went on prophylaxis with FVIII. All patients who successfully completed ITI have maintained tolerance with a mean follow-up of 101 months (range 7–168). Table I: Hemophilia A Failed ITI Successful ITI *One still ongoing Number of trials* 7 (23 %) 19 (73 %) African Americans 7 (41 %) 10 (59 %) Non-AA 0 10 (100 %) Historical Peak Titer (mean) 345 BU 47 BU Titer at Start of ITI (mean) 62 BU 5 BU Peak Titer on ITI (mean) 168 BU 46 BU Age at inhibitor development (mean) 26 months 12 months ITI with PD-FVIII 1 4 ITI with rFVIII 7 15 Hemophilia B During this time period, 2 boys with severe hemophilia B underwent ITI. Both had severe allergic reactions at the time of inhibitor development; both underwent desensitization successfully but both failed ITI. Both started ITI with plasma derived factor nine at age 15 months. One developed nephrotic syndrome while on ITI. Conclusions: Most patients with Hemophilia A were able to achieve and maintain tolerance (73%). Higher titer inhibitors, hemophilia B, younger age at development of inhibitor, AA race and treatment of bleeds with bypass agents or porcine factor while on ITI were risk factors for ITI failures. Loss of central venous access with recurrent infections was also a common reason for ITI failure.

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Jenny Goudemand ◽  
Chantal Rothschild ◽  
Virginie Demiguel ◽  
Christine Vinciguerrat ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Adjusted Relative Risk ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
End Point ◽  
History Of

Abstract Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.

Novel Treatment Approaches in Combination with Rituximab for Immune Tolerance Induction in Severe Hemophilia B.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3975-3975 ◽  
Author(s):  
Amanda M. Brandow ◽  
Rowena C. Punzalan ◽  
Karen Stephany ◽  
Craig Helsell ◽  
Joan C. Gill
Keyword(s):  
Immune Tolerance ◽  
High Titer ◽  
Tolerance Induction ◽  
Factor Ix ◽  
Hemophilia B ◽  
High Dose ◽  
Subdural Hemorrhage ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Novel Approaches

Abstract Although only 4–5% of patients with severe Hemophilia B (HB) develop factor IX (FIX) antibodies that cause inactivation of transfused FIX concentrate (conc), about 1/3 of these are associated with life-threatening anaphylactic reactions; immune tolerance induction (ITI) with high-dose FIX conc is often unsuccessful. We present individualized novel approaches to ITI in 2 boys with severe HB and high-responding inhibitors. ELISA assays utilizing recombinant FIX (rFIX) to capture patient IgG followed by detection with subclass specific monoclonal antibodies were developed to evaluate the characteristics of the factor IX inhibitors before, during and following ITI. Patient 1, a 2 yo boy, presented with a subdural hemorrhage; his inhibitor titer was 14 BU. He was treated with recombinant VIIa (rVIIa), 200 mcg/kg followed by 100 mcg/kg q2 hours plus rFIX conc (BeneFix), 1000 U/kg prior to and post subdural hematoma evacuation; a continuous infusion, 40U/kg/hour rFIX conc was started. FIX:C was >100%, so rVIIa was discontinued and the rFIX infusion was continued to maintain FIX:C levels above 50%. Rituximab (375 mg/m2 q week x 4) was started. On the 6th day, he developed anamnesis; plasma FIX:C dropped to the 20% range in spite of increases in his rFIX conc drip to 68 u/kg/hour. Investigation of right leg edema revealed a large thrombus involving the popliteal, iliac and inferior vena cava with pulmonary embolism. In order to remove the inhibitor antibody and achieve plasma FIX levels that would allow safe anticoagulation with heparin, plasmapheresis with an immunoadsorption Protein A sepharose column (Fresenius) was undertaken. FIX:C levels were unexpectedly lower immediately following each cycle. Investigation of FIX: Ag and anti-FIX IgG, IgG1 and IgG4 by ELISA assays before and after each cycle revealed the presence of FIX: Ag and specific anti-FIX IgG in the column eluates. After the 5th cycle, increasing FIX:C levels allowed weaning of the rFIX conc; the thromboses completely resolved. The patient currently is on standard prophylactic doses of rFIX conc with expected recoveries with no evidence of inhibitor. Patient 2 was a 9 year old boy with a high responding anaphylactoid inhibitor; he had severe and frequent hemarthroses treated with rVIIa with variable success resulting in significant hemophilic arthropathy. He had previously received 2 courses of rituximab with recurrence of inhibitor 3 weeks post-therapy. Therefore, in order to suppress T-cell as well as B-cell immune responses, after desensitization with increasing infusions of rFIX conc, he was treated with cyclophosphamide (10 mg/kg IV on days 2, 3 and PO on days 4 and 5) a standard course of rituximab (375 mg/m2 on days 1, 8, 15, 22), IVIG (100 mg/kg on days 2–5) initially, and high dose rFIX conc, 100U/kg/day. He is now maintained on every-other monthly doses of rituximab and replacement doses of IVIG. As FIX levels rose during ITI, rFIX conc was weaned; eight months after initiation of ITI, he has expected recoveries of FIX: C on standard prophylactic doses of rFIX conc. Investigation of the nature of the patient’s inhibitors revealed that both patients had high titer IgG1 and IgG 4 anti-factor IX antibodies that disappeared after ITI. Unlike the persistence of non-inhibitory IgG4 factor VIII antibodies reported in some patients with hemophilia A, in these two patients, there was no detectable FIX-specific pan-IgG, IgG1 or IgG4 following ITI. We conclude that novel approaches to ITI can be successfully undertaken in severe HB patients with high titer factor IX inhibitors.

Induction of Immune Tolerance in a 7-Year-Old Hemophiliac with an Anaphylactoid Inhibitor

1995 ◽  
Vol 74 (04) ◽  
pp. 1039-1041 ◽  
Author(s):  
James L Harper ◽  
Joan C Gill ◽  
Russell J Hopp ◽  
John Evans ◽  
William D Haire
Keyword(s):  
Antibody Titer ◽  
Immune Tolerance ◽  
High Purity ◽  
Hemophilia A ◽  
Rare Complication ◽  
Tolerance Induction ◽  
Skin Tests ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction

Summary Background: Anaphylactic reactions were a rare complication of low purity VIII concentrates, hut not with high purity VIII concentrates Case: 7 y/o WM with severe hemophilia A, received only cryoprecipitate and monoclonally purified VIII concentrates; developed post-infusional urticaria. A 2-Bethesda-unit inhibitor was detected. Generalized urticaria and bronchospasm following factor developed as the titer increased. Skin tests demonstrated reactivity to plasma derived VIII, but not recombinant VIII (rhVIII). Attempts at desensitization using rhVIII failed. KLISA revealed an anti-VIIl IgB antibody. He was treated with a modified tolerance regimen using rhVIII starting at 500 U/day with aggressive premedication. The dosage increased by 200 U weekly as tolerated to a maximum of l00U/kg/d without symptoms. Results: His antibody titer decreased rapidly once he started l00U/kg/d. Six months later, the inhibitor was <1 Bethesda unit. Conclusion: Immune tolerance induction using a graduated dosage of rhVIII was successful.

Congenital Bleeding Disorders

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 559-574 ◽  
Author(s):  
Margaret E. Rick ◽  
Christopher E. Walsh ◽  
Nigel S. Key
Keyword(s):  
Gene Transfer ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Von Willebrand Disease ◽  
Bleeding Disorders ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
History Of ◽  
Von Willebrand

Abstract Both clinical and basic problems related to the congenital bleeding disorders continue to confront hematologists. On the forefront are efforts to bring genetic correction of the more common bleeding disorders such as hemophilia A to the clinic in a safe and accessible manner. A second issue, particularly for patients with hemophilia, is the development of inhibitors—questions of how they arise and how to prevent and treat these problems that confound otherwise very successful replacement therapy and allow patients to maintain normal lifestyles. A third issue is the continuing question of diagnosis and management of von Willebrand disease, the most common congenital bleeding disorder, especially in individuals who have borderline laboratory values, but have a history of clinical bleeding. In Section I, Dr. Christopher Walsh discusses general principles of effective gene transfer for the hemophilias, specific information about viral vectors and non-viral gene transfer, and alternative target tissues for factor VIII and factor IX production. He highlights information about the immune response to gene transfer and reviews data from the hemophilia gene transfer trials to date. The future prospects for newer methods of therapy such as RNA repair and the use of gene-modified circulating endothelial progenitors are presented as possible alternatives to the more traditional gene therapy approaches. In Section II, Dr. Nigel Key focuses on inhibitor development in patients with hemophilia A. He reviews the progress in our understanding of the risk factors and presents newer information about the immunobiology of inhibitor development. He discusses the natural history of these inhibitors and the screening, laboratory diagnosis, and treatment, including the use of different modalities for the treatment of acute bleeding episodes. Dr. Key also presents information about the eradication of inhibitors by immune tolerance induction and reviews recent information from the international registries regarding the status and success of immune tolerance induction. In Section III, Dr. Margaret Rick discusses the diagnosis, classification, and management of von Willebrand disease. Attention is given to the difficulty of diagnosis in patients with mild bleeding histories and borderline laboratory test results for von Willebrand factor. She presents the value of different laboratory assays for both diagnosis and classification, and she relates the classification of von Willebrand disease to the choice of treatment and to the known genetic mutations. Practical issues of diagnosis and treatment, including clinical cases, will be presented.

scholarly journals What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 648-649 ◽  
Author(s):  
Maissaa Janbain ◽  
Steven Pipe
Keyword(s):  
Immune Tolerance ◽  
Half Life ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
History Of

Abstract A 10-year-old boy presents with a history of severe hemophilia A and high-titer inhibitor that had failed high-dose immune tolerance induction (ITI) with a recombinant factor VIII (rFVIII) product and a plasma-derived FVIII product. You are asked by his mother whether he should be tried on ITI with an extended half-life product, in particular, consideration of a rFVIIIFc concentrate.

scholarly journals Immune tolerance induction in patients with severe hemophilia A with inhibitors

2015 ◽  
Vol 50 (4) ◽  
pp. 248 ◽  
Author(s):  
Ji Eun Ryu ◽  
Young Shil Park ◽  
Ki Young Yoo ◽  
Kyoo Duck Lee ◽  
Yong-Mook Choi
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction

Low-dose immune tolerance induction in hemophilia A patients with inhibitors

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 983-988 ◽  
Author(s):  
EP Mauser-Bunschoten ◽  
HK Nieuwenhuis ◽  
G Roosendaal ◽  
HM van den Berg
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Low Dose ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
Two Factors ◽  
Inhibitor Level ◽  
Dose Factor

Abstract In patients with hemophilia A and inhibitory alloantibodies against factor VIII, various dosage schedules are used to obtain immune tolerance. In this study, we have evaluated the results of 13 years of low-dose immune tolerance induction and factors that are predictive of a positive result. The effect of immune tolerance induction in relation to age at inhibitor development, number of exposure days, age at start of therapy, maximum inhibitor titer, factor VIII products involved, and virologic status were determined. We evaluated 24 patients with severe hemophilia A and inhibitors who were treated with regular infusions with low-dose (25 U/kg every other day) factor VIII to obtain immune tolerance. In 21 of 24 patients (87%), immune tolerance induction was successful. The response time was determined by two factors: the highest inhibitor level and the age at inhibitor development. In patients with maximum inhibitor levels of less than 40 Bethesda units (BU)/mL, immune tolerance was obtained sooner than in patients with inhibitor levels exceeding 40 BU/mL (P = .005). Patients in whom an inhibitor developed before the age of 2.5 years also tended to have a quick immune response (P = .014). Immune tolerance with low-dose factor VIII is often successful in hemophilia A patients with inhibitors. Young children and patients with maximum inhibitors of less than 40 BU/mL show a relatively rapid response.

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