First‐line immune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors' Organisation Inhibitor and Paediatric Working Parties

Collins, Peter William; Chalmers, Elizabeth; Alamelu, Jayanthi; Hay, C. R. M.; Liesner, Ri; Makris, Mike; Mathias, Mary; Payne, Jeanette; Rangarajan, Savita; Richards, Michael; Talks, Kate; Tunstall, Oliver; Williams, Michael D.; Hart, Daniel P.

doi:10.1111/hae.13264

Cited by 25 publications

(38 citation statements)

References 18 publications

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“…Given this, it is important that inhibitor titre testing and monitoring including joint status and bleed phenotype be performed on a frequent (eg, monthly) basis, and dose/frequency escalation should be considered based on a substantial rise in inhibitor titres or the occurrence of significant bleeding. We concur with the approach taken by the UKHCDO group, which indicated that low‐risk patients who commence a low‐dose ITI regimen (50 U/kg on alternate days) should be escalated to 100 U/kg daily should their inhibitor titre rise to >40 BU and for those patients commencing on 100 U/kg daily that their regimen should be escalated to 200 U/kg daily if their inhibitor titres rise to >200 BU while on ITI …”

Section: Part A: Fit Group Appraisal Of Current Itisupporting

confidence: 78%

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Carção

Escuriola‐Ettingshausen²,

Santagostino³

et al. 2019

Haemophilia

138

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IntroductionAs a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non‐factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed.AimThe Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors.Discussion and ConclusionsDespite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non‐factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low‐dose/low‐frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further.

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Section: Part A: Fit Group Appraisal Of Current Itisupporting

confidence: 78%

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Carção

Escuriola‐Ettingshausen²,

Santagostino³

et al. 2019

Haemophilia

138

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“…Immune tolerance induction (ITI) therapy is the most established treatment to eradicate inhibitors. Guidelines suggest that the ITI regimen should be stratified based on pre‐ITI Bethesda titer using an escalating dose of FVIII (50 IU/kg every other day [QOD] to 100 IU/kg twice daily) . Although low‐dose ITI regimen (FVIII 50 IU/kg thrice weekly or QOD) is recommended only for low‐titer inhibitors, this regimen of relatively lower cost is the only widely acceptable therapy in China with economic constraint.…”

Section: Introductionmentioning

confidence: 99%

“…[QOD] to 100 IU/kg twice daily). [3][4][5] Although low-dose ITI regimen (FVIII 50 IU/kg thrice weekly or QOD) is recommended only for low-titer inhibitors, this regimen of relatively lower cost is the only widely acceptable therapy in China with economic constraint.…”

Section: Introductionmentioning

confidence: 99%

Low‐dose immune tolerance induction for children with hemophilia A with poor‐risk high‐titer inhibitors: A pilot study in China

Chen

Cheng

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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BackgroundImmune tolerance induction (ITI) therapy is currently unaffordable in China. Management of hemophilia A children with high‐titer inhibitor is therefore a challenge.AimTo describe the ITI strategy using plasma‐derived factor VIII/von Willebrand factor concentrate (pdFVIII/VWF) +/− immunosuppression and to report its efficacy in children with hemophilia A having poor‐risk status for ITI success.MethodsA prospective pilot study on children with hemophilia A having poor‐risk status (all with at least inhibitor titer > 10 BU pre‐ITI initiation). Patients received ~50 IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab +/− prednisone.ResultsSixteen patients with median age 2.9 (range, 2.2‐13.2) years and median pre‐ITI inhibitor titer 30.7 (range, 10.4‐128) BU were enrolled. Analysis at median 14.7 (range, 12.4‐22.6) months’ follow‐up showed a total response rate of 87.5%. This included success (achieving inhibitor < 0.6 BU) in 13 patients (81.3%) in a median of 8.8 (range, 3.2‐11.8) months, and partial success (achieving inhibitor < 5 BU but > 0.6BU) in 1 (6.3%). Compared to the pre‐ITI period, the mean bleeds/month during ITI was 0.51 (64.0% reduction), and joint bleeds/month was 0.34 (64.3% reduction). This low‐dose ITI strategy cost less by 70% to 87% than that for the high‐dose FVIII regimen. No severe adverse events were observed.ConclusionThis low‐dose ITI strategy of pdFVIII/VWF +/− immunosuppression achieved relatively satisfactory outcomes in children with hemophilia A inhibitor having poor‐risk status. This low‐dose regimen showed economic advantages and is therefore suitable for using in China. However, further study in a larger cohort with a longer follow‐up time is needed.

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“…Specific thresholds are suggested for both outcomes to define success or partial success . Very recently, a more pragmatic application of PK to tailor the dose during ITI in children was suggested by the UK Haemophilia Centre Doctors’ Organisation (UKHCDO) that uses only trough level and mitigates the need to take multiple samples to assess both recovery and half‐life . Calculating the half‐life or measuring the recovery or trough level of the infused factor constitutes a (simplified) PK approach to tailoring individual treatment.…”

Section: Established Uses Of Pk Measures In Routine Clinical Care Of mentioning

confidence: 99%

Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations

Iorio

Edginton

Blanchette

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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ObjectivesIn a separate document, we have provided specific guidance on performing individual pharmacokinetic (PK) studies using limited samples in persons with hemophilia with the goal to optimize prophylaxis with clotting factor concentrates. This paper, intended for clinicians, aims to describe how to interpret and apply PK properties obtained in persons with hemophilia.MethodsThe members of the Working Party on population PK (PopPK) of the ISTH SSC Subcommittee on Factor VIII and IX and rare bleeding disorders, together with additional hemophilia and PK experts, completed a survey and ranking exercise whereby key areas of interest in the field were identified. The group had regular web conferences to refine the manuscript’s scope and structure, taking into account comments from the external feedback to the earlier document.ResultsMany clinical decisions in hemophilia are based on some form of explicit or implicit PK assessment. Individual patient PK profiles can be analyzed through traditional or PopPK methods, with the latter providing the advantage of fewer samples needing to be collected on any prophylaxis regimen, and without the need the for a washout period. The most useful presentation of PK results for clinical decision making are a curve of the factor activity level over time, the time to achieve a certain activity level, or related parameters like half‐life or exposure (AUC). Software platforms have been developed to deliver this information to clinicians at the point of care. Key characteristics of studies measuring average PK parameters were reviewed, outlining what makes a credible head‐to‐head comparison among different concentrates. Large data collections of PK and treatment outcomes currently ongoing will advance care in the future.ConclusionsTraditionally used to compare different concentrates, PK can support tailoring of hemophilia treatment by individual profiling, which is greatly simplified by adopting a PopPK/Bayesian method and limited sampling protocol.

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First‐line immune tolerance induction for children with severe haemophilia A: A protocol from the UK Haemophilia Centre Doctors' Organisation Inhibitor and Paediatric Working Parties

Cited by 25 publications

References 18 publications

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Low‐dose immune tolerance induction for children with hemophilia A with poor‐risk high‐titer inhibitors: A pilot study in China

Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations

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