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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 13
| Issue : 2 | Page : 91-94 |
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Immune tolerance induction experience from a single institute in the United Arab Emirates
Najam Ahmed Muhammad Ahmed Awan, Layla Ali Eisa Mohamed Alreyami, Asia Ahmad Abdallah Al Mulla, Majed Mohammed Alremeithi, Muhammad Faisal Khanani
Department of Hematology Oncology, Tawam Hospital, Al Ain, UAE
| Date of Submission | 11-Mar-2022 |
| Date of Decision | 09-Apr-2022 |
| Date of Acceptance | 22-Apr-2022 |
| Date of Web Publication | 04-Aug-2022 |
Correspondence Address:
Dr. Najam Ahmed Muhammad Ahmed Awan
Department of Hematology Oncology, Tawam Hospital, Al Ain
UAE
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/joah.joah_24_22
BACKGROUND: Immune tolerance induction (ITI) is the gold standard approach for eradicating inhibitors and increasing patient tolerance to factor VIII. The success rate of ITI may vary depending on patient variables and factors relating to the pattern of treatment for the induction of immune tolerance. Children with recently diagnosed inhibitors are the best candidates for ITI, and those with favourable expected results should be offered ITI as soon as inhibitors are identified. Recombinant factor VIII Fc fusion protein has proved a therapeutic advantage in patients with high factor VIII inhibitor titers
AIMS AND OBJECTIVES: To evaluate the clinical characteristics and outcomes of ten hemophilic pediatric patients who underwent ITI therapies to eliminate FVIII inhibitors at Tawam Hospital, UAE
MATERIALS AND METHODS: The data of ten hemophilia A children aged 2–7 years with high inhibitor titers who underwent ITI therapy at Tawam Hospital, UAE, were retrospectively collected for this case series. A comparison of bleeds before and after the ITI therapy was also made. Patients with either failed or partially successful primary ITI therapy underwent rescue ITI therapy. Data analysis was performed using SPSS version 26.
RESULTS: Full success was achieved in 60% (6/10) of the patients, 10% (1/10) achieved partial success, whereas 30% (3/10) failed the primary ITI therapy. The rescue ITI therapy was successful in 50% (2/4) of the patients and the remaining 50% (2/4) achieved partial success [Table 2]. The rescue ITI was successful in 66% (2/3) of those patients who received Elocta and partially successful in 33% (1/3)
CONCLUSION: ITI therapy is the gold standard for the eradication of antibodies against FVIII. The patients with good expected outcomes should be offered ITI as soon as the inhibitors are confirmed. The use of extended half life rFVIIIFc demonstrated therapeutic benefit, particularly in challenging ITI patients with high inhibitor titers
Keywords: Bleed, eradication, FVIII replacement therapy, immune tolerance induction, inhibitors
How to cite this article:
Ahmed Awan NA, Mohamed Alreyami LA, Al Mulla AA, Alremeithi MM, Khanani MF. Immune tolerance induction experience from a single institute in the United Arab Emirates. J Appl Hematol 2022;13:91-4 |
How to cite this URL:
Ahmed Awan NA, Mohamed Alreyami LA, Al Mulla AA, Alremeithi MM, Khanani MF. Immune tolerance induction experience from a single institute in the United Arab Emirates. J Appl Hematol [serial online] 2022 [cited 2023 Sep 22];13:91-4. Available from: https://www.jahjournal.org/text.asp?2022/13/2/91/353278 |
| Introduction | |  |
The development of antibodies to factor VIII is a treatment-related complication of hemophilia A, which makes the replacement therapy ineffective and increases the financial cost. Eradication of inhibitors by immune tolerance induction (ITI) is the standard of care to restore the efficacy of the FVIII replacement therapy.[1] ITI should be initiated as soon as an inhibitor is confirmed. Host variables such as lower pre-ITI, historic and peak titers, and young age at the time of therapy initiation have been associated with higher success rates. Other variables such as ethnicity, mutation, dosage, and product type have demonstrated varying outcomes. Concomitant use of immunomodulators such as cyclophosphamide has been discontinued due to potential side effects, but the use of rituximab during ITI for immunosuppression is still being explored.[2] Emicizumab is a recombinant monoclonal antibody that has been associated with significantly fewer bleeding events when prophylactically administered to hemophilia A patients with inhibitors; nonetheless, ITI remains the gold standard for their management.[3] Retrospective cohort studies and registries have demonstrated ITI success rates of 57%–91% and 67%–79%, respectively. ITI is considered to be successful if there is a persistently negative inhibitor titer (<0.6 BU mL_1), FVIII recovery ≥66% of expected, and FVIII half-life ≥6 h, whereas partially successful if, after 33 months of ITI, there is a negative inhibitor titer but persistently abnormal FVIII recovery or half-life.[2] Another promising therapeutic choice includes the use of recombinant factor VIII Fc fusion protein (rFVIIIFc), which results in reduced immune response in hemophilia A patients.[4] In addition, when used in the first ITI cycle, rFVIIIFc results in rapid time to tolerization in high-risk patients, as well as improved outcomes among rescue ITI patients with previously failed ITI using other products.[5] ITI therapy has a high cost, but its beneficial impact on the lifelong care of these patients improved life expectancy and quality makes it justifiable. Here, we report a case series of ten hemophilic patients who underwent ITI at Tawam Hospital, UAE.
| Methods | | |
The data of ten hemophilia A children aged 2–7 years with high inhibitor titers who underwent ITI therapy at Tawam Hospital, UAE, were retrospectively collected for this case series. Demographic and clinical data were obtained from medical records. The case series protocol was approved by the Institutional Review Board of the Tawam Hospital.
None of the patients had any known comorbidity or chronic infectious disease. Historic, peak, and pre-ITI titers of each patient were recorded, in addition to the age at ITI therapy initiation and duration between diagnosis and therapy initiation. Duration of the therapy and type of FVIII used before and after the therapy were captured. In addition, dosage, hemorrhagic events, and central venous catheter (CVC) infections were also noted. Data analysis was performed using SPSS version 26 (IBM Corp., Armonk , NY, USA).
ITI was termed successful in cases with persistently negative inhibitor titer (<0.6 BU mL_1), FVIII recovery ≥66% of expected value, and partially successful with negative inhibitor titer (<0.6 BU mL_1), but FVIII recovery was <66% of the expected value. A comparison of bleeds before and after the ITI therapy was also made. Patients with either failed or partially successful primary ITI therapy underwent rescue ITI therapy.
| Results | | |
A total of ten children were included in this case series, with a mean age of 3.77 (2–7) years at the time of ITI therapy initiation. The median historic and therapy initiation titers were 165 (35–1000) BU/ml and 87.5 (20–950) BU/ml, respectively. Six patients developed inhibitors against FVIII on Kogenate, whereas four developed inhibitors on Xyntha, and none of the patients developed inhibitors on Elocta. The ITI therapy was started within a mean period of 3 (2–4) weeks from the diagnosis. The median peak titer during the primary ITI therapy was 450 (100–2000) BU/ml, and the mean duration of the primary therapy was 17.2 (12–36) months. No hemorrhagic events were recorded during the primary ITI cycle. A median dose of 100 (75–200) IU/kg three times a week of FVIII was administered.
Full success was achieved in 60% (6/10) of the patients, 10% (1/10) achieved partial success, whereas 30% (3/10) failed the primary ITI therapy.
Kogenate, Elocta, and Xyntha were administered to 40% (4/10), 30% (3/10), and 30% (3/10) of the patients, respectively, during the primary ITI therapy [Table 1]. Rituximab was used as an immune modulator for two patients on Elocta during primary ITI. CVC infections were developed in 70% (7/10) of the patients during the primary ITI therapy. | Table 1: Preimmune tolerance induction and primary immune tolerance induction therapy data
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Four patients underwent rescue ITI therapy. Seventy-five percent (3/4) of those patients received Elocta and 25% (1/4) received Wilate. The rescue ITI therapy was successful in 50% (2/4) of the patients and the remaining 50% (2/4) achieved partial success [Table 2]. The rescue ITI was successful in 66% (2/3) of those patients who received Elocta and partially successful in 33% (1/3). The rescue ITI therapy patient who received Wilate achieved a partial success.
The mean number of bleeds per year before and after the ITI therapy was 12.9 (9–20) and 3.2 (1–6), respectively [Table 3], whereas the number of target joints involved before and after the ITI was 1.9 (1–3) and 2.0 (1–3), respectively. | Table 3: Bleeding frequencies preimmune tolerance induction therapy and postimmune tolerance induction therapy
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Furthermore, the mean period of absence from school for the patients was 5.8 (4–12) months [Table 1].
| Discussion | | |
The current case series reported the clinical characteristics and outcomes of ten hemophilic pediatric patients who underwent ITI therapies to eliminate FVIII inhibitors. All of the patients were ≤7 years of age with high antibody titers (>10 BU). Lower titer levels and young age at therapy initiation have consistently been used to predict ITI success.[2] Nonetheless, three of our patients had very high historic, pre-ITI, and peak inhibitor titers (>500 BU), of which 66.67% (2/3) had a successful primary ITI therapy using Elocta. Thus, this study seconds younger age at the time of ITI therapy initiation as a good outcome predictor, but ITI therapies were successful even in patients with higher titer levels when rFVIIIFc (Elocta) was used.
A higher CVC infection rate was found in our report. International ITI study also reported CVC infections as the most common complication particularly associated with younger age, which did not affect the therapy outcome.[6]
The treatment cost for hemophilia patients with FVIII inhibitors is 3.3 times higher than patients without inhibitors.[7] Despite the complications and factor cost, patients who undergo ITI therapy have lower lifetime treatment costs than those treated on demand, in addition to longer life expectancy, improved quality of life, and decreased bleeding events.[8]
ITI therapy is the gold standard for the eradication of antibodies against FVIII; however, alternative treatment choices including nonfactor replacement agents such as emicizumab and concizumab need to be further evaluated.[3]
This report has limitations as the sample size is small, and only ten pediatric patients were enrolled. The outcomes need to be confirmed by a large sample study for the Arab patient population.
| Conclusion | | |
ITI therapy is the gold standard for the eradication of antibodies against FVIII. The patients with good expected outcomes should be offered ITI as soon as the inhibitors are confirmed. The use of extended half-life rFVIIIFc demonstrated therapeutic benefit, particularly in challenging ITI patients with high inhibitor titers, which could be due to its potential immunological properties that need to be confirmed through large prospective studies.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Rocino A, Cortesi PA, Scalone L, Mantovani LG, Crea R, Gringeri A; European Haemophilia Therapy Strategy Board (EHTSB); European Haemophilia Therapy Strategy Board EHTSB. Immune tolerance induction in patients with haemophilia a and inhibitors: Effectiveness and cost analysis in an European Cohort (The ITER Study). Haemophilia 2016;22:96-102.  |
| 2. | Valentino LA, Kempton CL, Kruse-Jarres R, Mathew P, Meeks SL, Reiss UM, et al. US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. Haemophilia 2015;21:559-67. |
| 3. | Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017;377:809-18. |
| 4. | Janbain M, Pipe S. 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 Am Soc Hematol Educ Program 2016;2016:648-9. |
| 5. | Carcao M, Shapiro A, Staber JM, Hwang N, Druzgal C, Lieuw K, et al. Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis. Haemophilia 2018;24:245-52. |
| 6. | Rodriguez V, Mancuso ME, Warad D, Hay CR, DiMichele DM, Valentino L, et al. Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: Lessons from the international immune tolerance study. Haemophilia 2015;21:e369-74. |
| 7. | Rocha P, Carvalho M, Lopes M, Araújo F. Costs and utilization of treatment in patients with hemophilia. BMC Health Serv Res 2015;15:484. |
| 8. | Earnshaw SR, Graham CN, McDade CL, Spears JB, Kessler CM. Factor VIII alloantibody inhibitors: Cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment. Haemophilia 2015;21:310-9. |
[Table 1], [Table 2], [Table 3]
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