Challenges in the Diagnosis and Management of Hemophilia ?· ISTH Advanced Training Course Dubai, UAE…

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ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training Course

Challenges in the Diagnosis and Management of

Hemophilia

Nigel Key, MB ChB FRCP

ISTH Advanced Training CourseDubai, UAE

Disclosures for Nigel Key In compliance with COI policy, ISTH requires the following disclosures to the session audience:

Research Support/P.I. NIH/NHLBI; Doris Duke Foundation; Baxalta/Shire

Employee No relevant conflicts of interest to declare

Consultant CSl Behring; Baxalta/Shire; Genentech/Roche; Novo Nordisk

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria No relevant conflicts of interest to declareScientific Advisory

Board RTI International

Presentation includes discussion of the following off-label use of a drug or medical device:None

- 2 -

ISTH Advanced Training CourseDubai, UAE

Outline Factor VIII Assays One-stage vs. chromogenic

When Phenotype and Factor Levels Dont Agree Severe hemophilia A Non-severe hemophilia A

Prophylaxis and Personalized Medicine Pharmacokinetic heterogeneity Monitoring replacement therapy

Inhibitors and Novel Therapies SIPPET study Disruptive technologies, e.g. Emicizumab

- 3 -

ISTH Advanced Training CourseDubai, UAE

One-Stage FVIII Assay

Reference plasma

100% of all factorsSubstrate plasma

0% FVIII, 100% all othersPatient plasma

? FVIII

ISTH Advanced Training CourseDubai, UAE

One-Stage FVIII Assay

Reference +

Substrate

Patient+

Substrate

1:10 1:20 1:40 1:80 1:160

aPTT

aPTT

ISTH Advanced Training CourseDubai, UAE

One-Stage FVIII Assay

50

60

70

80

90

100

12 24 48 96

aPTT

(s)

Concentration %

Reference

Kotke-Marchant 2008

ISTH Advanced Training CourseDubai, UAE

Chromogenic FVIII Assay

Intrinsic pathway

Extrinsic pathway

XII

XI

IX

X XXa

VIII

VII

Thrombin

Fibrin

Clot

V

ISTH Advanced Training CourseDubai, UAE

Chromogenic FVIII Assay: Add Reagent Cocktail Generate Factor Xa

Intrinsic pathway

Extrinsic pathway

XII

XI

IXa

X XXa

VIII

VII

Thrombin

Fibrin

Clot

V

Xa

ISTH Advanced Training CourseDubai, UAE

Add Chromogenic Substrate to Measure Generated Factor Xa

Intrinsic pathway

Extrinsic pathway

XII

XI

IX

X XXa

VIII

VII

Thrombin

Fibrin

Clot

V

ISTH Advanced Training CourseDubai, UAE

Why Should the Clinician Care about Which FVIII Assay is Used?

Maintaining target trough levels in the 1-5% range depends on accurate assessment of factor activity in plasma

Assay details are increasingly important:

aPTT-based one-stage assays use various activators Silica Ellagic acid Kaolin.

Chromogenic assays At least 3 on the market variable method/reagents

ISTH Advanced Training CourseDubai, UAE

Why Should the Clinician Care about Which FVIII Assay is Used?

Maintaining target trough levels in the 1-5% range depends on accurate assessment of factor activity in plasma

Assay details are increasingly important:

aPTT-based one-stage assays use various activators Silica greatly over-estimates activity of Novo8-GP product Ellagic acid Kaolin.

Chromogenic assays At least 3 on the market variable method/reagents

ISTH Advanced Training CourseDubai, UAE

Know Your Product!

http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM503560.pdf. Accessed July 2016.

ISTH Advanced Training CourseDubai, UAE

Mild Bleeding Phenotype:- < 2 bleeding episodes/year- median lifelong concentrate consumption < 500 IU/kg

Severe Bleeding Phenotype:- > 25 bleeding episodes/year- median lifelong concentrate consumption > 2000 IU/kg

ISTH Advanced Training CourseDubai, UAE

Thrombin Generation Testing

ISTH Advanced Training CourseDubai, UAE

ISTH Advanced Training CourseDubai, UAE

Variability in Clinical Phenotype of Severe Hemophilia: Age at First Joint Bleed

In a study of 171 patients (2,166 patient-years of follow-up), those who experienced their first joint bleed later needed less treatment and developed less arthropathy

Onset of joint bleeding was inversely related to treatment requirement and may serve as an indicator of clinical phenotype

van Dijk K, et al. Haemophilia. 2005;11:438-443..

16

ISTH Advanced Training CourseDubai, UAE

Discrepant Mild Hemophilia A

In mild & moderate hemophilia A: At least a two-fold discrepancy between one-stage and

chromogenic assay in up to 40% of cases, most of which are below normal limits of FVIII for both assays, but A subset that shows normal one stage and aPTT, but reduced activity

by two-stage testing (5-10% of mild hemophilia A patients) Bleeding symptoms are usually in accord with the two-

stage/chromogenic assay result Opposite has also been described to occur (reduced one-stage, and

normal chromogenic) At least some of these cases are not associated with a bleeding

disorder (investigated with incidental prolonged aPTT)

ISTH Advanced Training CourseDubai, UAE

Western Denmark Study

109 patients with mild hemophilia A 92 patients/53 unrelated families

Baseline FVIII levels measured by both assays

Poulsen AL 2009;15:285Poulsen, AL. Haemophilia. 2009

ISTH Advanced Training CourseDubai, UAE

Chromogenic/1-Stage Assay Ratios

Poulsen, AL. Haemophilia. 2009

ISTH Advanced Training CourseDubai, UAE

Prophylaxis in Hemophilia; ISTH Definitions

Blanchette VS, Key NS, et al. J Thromb Haemost. 2014;12(11):1935-1939.

ISTH Advanced Training CourseDubai, UAE

PK Parameters Determining Bleeding Frequency in Hemophilia

Area under the curve

Peak following infusion

Trough

Time

Perc

ent F

acto

r Lev

el

Infusion

Adequate Hemostasis Range

Adequate hemostasis range May help prevent

activity-related bleeds

Area under the curve May help prevent

subclinical bleeding

Trough Determines

spontaneous bleeding risk

Collins PW, et al. Haemophilia. 2011;17(1):2-10. Collins PW. Haemophilia. 2012; 18 (Suppl. 4):131135.Collins PW, et al. J Thromb Haemost. 2010;(2):269-275. Blanchet VS, et al. JTH. 2009; 7(Suppl. 2):5455.

ISTH Advanced Training CourseDubai, UAEden Uijl et al. Haemophilia. 2011;17(1):41-44; den Uijl et al. Haemophilia 2011; 17(6): 849-53

Annual Number of Joint Bleeds According to Baseline FVIII Level

ISTH Advanced Training CourseDubai, UAE

Factor Dosing: Comparison of FVIII Half-Life for (Non Inhibitor) Patients on 5th and 95th Percentiles

Collins PW, et al. Haemophilia. 2011;17(1):2-10.

ISTH Advanced Training CourseDubai, UAE

Individual Variation of rFVIII-Fc Half Life

Hours After Infusion

Fact

or A

ctiv

ity (%

)

Data courtesy of Stacy E. Croteau, MD, MMS.

ISTH Advanced Training CourseDubai, UAE

Plasma VWF Level is Critical in Determining Inter-Individual PK Variability

Clearance Half Life

Powell JS, et al. Blood. 2012;119(13):3031-3037.Zourikian N, et al. Haemophilia. 2016;22(3):e177-183.

ISTH Advanced Training CourseDubai, UAE

Determinants of Breakthrough Bleeding Frequency on 3x per Week FVIII Prophylaxis

Annualized bleeding rate (ABR) significantly correlated with VWF:Ag (p=0.038) and with age (p = 0.021)

AUC and T1/2 increased with increased VWF:Ag(p

ISTH Advanced Training CourseDubai, UAELalezari S. Haemophilia 2014:19;e15

Determinants of Breakthrough Bleeding Frequency on 3x Per Week FVIII Prophylaxis

ISTH Advanced Training CourseDubai, UAE

Factor Level and Bleed RiskProphylaxis Model: FVIII dosing to prevent spontaneous

bleeds

Collins PW, et al. J Thromb Haemost. 2009;7:413-420.

Pred

icte

d Bl

eeds

per

Yea

r

Time With Factor VIII Below 1 IU dL-1, h/wk-1

ISTH Advanced Training CourseDubai, UAE

Activity Increases Risk

Broderick CR, et al. JAMA. 2012;308(14):1452-1459.

Inactive or No Expected Collisions

Chance of Significant Collisions

Significant Collisions are Inevitable

95% CI

ISTH Advanced Training CourseDubai, UAE

Survey of Inhibitors in Plasma Product Exposed Toddlers (SIPPET) Study

Study of inhibitor formation rates

Screening Age < 6y Plasma FVIII activity < 1% No previous FVIII concentrate treatment (PUPs) Blood component exposure < 5 times

Randomized for FVIII replacement

Peyvandi F, et al. N Engl J Med. 2016 May 26;374(21):2054-2064.

Plasma derived (pdFVIII, n = 125)

Recombinant (rFVIII, n = 126)

ISTH Advanced Training CourseDubai, UAE

SIPPET Results

High titer (peak > 5 BU/ml) pdFVIII: 18.6% rFVIII: 28.4% HR: 1.69

Peyvandi F, et al. N Engl J Med. 2016 May 26;374(21):2054-2064.