Current Thinking in Haemophilia - Prophylaxis Dr Julia Phillips - - PowerPoint PPT Presentation

Current Thinking in Haemophilia - Prophylaxis

Dr Julia Phillips Wellington, NZ

Acute bleeds in severe haemophilia

 Predominantly into

joints and muscle

 Painful

Chronic musculoskeletal damage

 Quality of life is

associated with

• rthopaedic status

in people with haemophilia

Scalone L. et al Haemophilia 2006;12:154-162

Prophylaxis

 “Regular infusions of factor

concentrate given for more than 2 months with the intention of preventing bleeding and the musculoskeletal complications of bleeding”

Rationale for prophylaxis

 People with moderate haemophilia (1-5%) have

fewer musculoskeletal complications than people with severe haemophilia (<1%)1

 Converting severe haemophilia to moderate

haemophilia with factor replacement would reduce the incidence of musculoskeletal complications2

1. Ahlberg A. Acta Orthop Scand 1965;77(S):3-132. 2. Nilsson IM et al. J Int Med 1992;232:25-32

Prophylaxis

Primary started before the second large joint bleed and before age 3 yrs Secondary started after 2 or more large joint bleeds or after age 3 yrs Tertiary started after the onset of joint disease Intermittent given to prevent bleeding for short periods of time

WFH guidelines for the management of hemophilia 2012

Prophylaxis

 Severe haemophilia A (and B)

• primary
• secondary
• tertiary

 Haemophilia with inhibitors

Primary prophylaxis

Swedish experience

 Primary prophylaxis in severe

haemophilia since 1958

 Start before 1st joint bleed  Usually age 1-3 yrs

Nilsson IM et al. J Intern Med 1992;232:25-32.

Swedish prophylaxis

Factor dose Frequency Haemophilia A 25-40 iu/kg iv 3-4 x per week Haemophilia B 25-40 iu/kg iv 2 x a week

Nilsson IM et al. J Intern Med 1992;232:25-32.

Swedish experience

Nilsson IM et al. J Intern Med 1992;232:25-32. Age at evaluation 3-6 yr 7-12 yr 13-17 yr 18-23 yr 24-32 yr Number of pts 6 9 20 10 15 Mean age at start of treatment 1.1 1.2 2.6 4.9 7.0 Annual joint bleeds 0.1 0.1 3 5.6 5.0 Orthopaedic joint score 0 1.2 2.9 6.6 Radiologic joint score 4.8 14.2 20.6

Swedish experience

After 25 years:-

 Full dose prophylaxis (FVIII/IX >1%) was

100% effective in preventing arthropathy

 Less than full dose prophylaxis or late

prophylaxis did not completely prevent significant arthropathy

Nilsson IM et al. J Intern Med 1992;232:25-32.

Joint outcome study

 65 boys with severe haemophilia A  Age <30 months  Randomised to primary prophylaxis or

‘enhanced’ on demand therapy

 Evaluated for bleeding and joint

damage at age 6 yrs

Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Joint outcome study

Prophylaxis

 25-40 iu/kg iv alternate days

Enhanced on demand

 40 iu/kg iv initially, 20 iu/kg iv @ 24

and 72 hrs.

Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Joint outcome study

 Significantly fewer joint and overall

bleeding episodes were seen in prophylaxis group (p<0.001 for both)

Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Joint outcome study

Proportion of subjects with no MRI evidence of joint damage at age 6yrs:-

 prophylaxis arm – 93%  episodic arm – 55%

P = 0.002

Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

JOS - Conclusions

 Prophylaxis is superior to enhanced

episodic therapy in preventing bleeding and joint disease in young boys with haemophilia A

Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Intracranial haemorrhage

 Nested case control

study

 Prrescribed

prophylaxis was associated with a 50% reduction in ICH

Witmer C et al. Br J Haem 2011;152(2):211-216

Educational achievement

 131 children with haemophilia treated at

various US centres on demand or on prophylaxis

 Those with less than 12 bleeds in the year

before enrolment had significantly greater scores on mathematics, reading and overall achievement

Shapiro AD et al. Pediatrics 2001;108:e105

Benefits of prophylaxis

 Decreases bleeding episodes, haemophilic

arthropathy, longterm morbidity1-3

 Reduces emergency room visits and

hospitalisations3

 Improves capacity for physical activity, school

attendance and academic performance1,4

 Improves quality of life3  Enables people to live more normal lives1

1. Thornburg CD. Pipe SW. Hemophilia 2006:12:198-94. 2. Manco-Johnson MJ et al. NEJM 2007;357:535-544 3. Panicker J et al. Hemophilia 2003;9:272-278 4. Shapiro AD et al. Pediatrics 2001;108:e105.

Does early prophylaxis increase inhibitor formation?

Gouw SC Blood 2007;109:4648-4654

Challenges

Central access?

Factor usage

Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Prophylactic approaches in severe haemophilia A

FVIII Dose Start Sweden 25-40 iu/kg iv 3-4 x per week Before first joint bleed Dutch 15-30 iu/kg iv 3 x per week After first joint bleed Canada 50 iu/kg iv weekly escalating to 30 iu/kg iv 2 x per week and 25 iu/kg iv alt days After first joint bleed

Canadian vs Swedish

25 boys after 5 yrs on Canadian prophylaxis cf JOS ‘Swedish’ prophylaxis

2 x haemarthroses at 1.2 pa More target joints All clinically normal joints Little radiological arthropathy Osteochondral changes in 50% on MRI

Feldman et al. J Thromb Haemost 2006;4(6):1228-1236..

What is the optimal prophylactic regimen?

Breakthrough bleeds correlate with time at low FVIII levels

Collins PW et al. J Thromb Haemost 2009;7:413-20 Age 1-6 yrs, n = 44 10-65 yrs n = 99 Age 1-6 yrs, n = 44

Pharmacokinetics

500 iu daily 1000 iu MWF + 500 iu Sunday 1000 iu alternate days 1000 iu MW, 1500 iu Friday P Collins

PK – Individual variation

0.5 1 1.5 2 2.5 10 20 30 40 50 60 Hours after infusion log FVIII level (%)

Half life = approx 15 hrs Recovery = 122% Half-life = approx 6.5 hrs

0.5 1 1.5 2 2.5 5 10 15 20 25 30 Hours after infusion Log FVIII level

Recovery = 140%

Population PK

Bjorkman S et al. Blood 2012;119(2):612-618.

Does prophylaxis need to be personalised?

Bleeding in relation to baseline FVIII levels

Den Uijl I et al Haemophilia 2011;17:41-4

Subclinical bleeding

Is a 1% trough level the right target?

Duration of primary prophylaxis

 European survey  92/218 (42%) discontinued

prophylaxis in adolescence

 26/92 (28%) restarted

Richards M et al. Haemophilia 2007;13:473-479.

“Prophylaxis in haemophilia should be lifelong”

M Makris. Blood Transfusion 2012;10(2):165- 8.

Secondary prophylaxis

WFH “Regular continuous treatment started after 2 or more large joint bleeds but before the onset of joint disease.”

ESPRIT

 40 boys median age 48-50 months,  no clinical or radiographic evidence of

arthropathy

 25 iu/kg FVIII iv x 3 per week

adjusted up for bleeding or to achieve trough level of 1%, up to 40 iu/kg vs

• n demand

Gringeri A et al. J Thromb Haemost 2011;9(4):700-710

ESPRIT

Prophylaxis group had:-

 Fewer bleeds  Fewer joint bleeds  Less radiographc evidence of

arthropathy

 Significantly better QOL

Gringeri A et al. J Thromb Haemost 2011;9(4):700-710

Prophylaxis in resource poor environment

 66 patients with severe haemophilia A  Secondary prophylaxis  FVIII 10 iu/kg x 2 per week

Tang L et al. Haemophilia 2013;19:27-34.

Prophylaxis in resource poor environment

 Bleeding significantly reduced

• 79% less joint bleeding (p<0.01)
• 69% less severe bleeding (p<0.01)

 No increase in factor consumption

compared to on-demand management.

Tang L et al. Haemophilia 2013;19:27-34.

Tertiary prophylaxis

WFH “Regular continuous treatment started after the onset of joint disease to prevent further damage.”

Orthopedic outcome study

 673 people  Severe haemophilia

A with established joint disease

 +/- Prophylaxis  Observed for 6 yrs

Prophylaxis group suffered less progression of arthopathy clinically and radiologically

Aledort LM et al. J Int Med 1994;236:391-399.

SPINART

 84 subjects, aged 12-50 yrs.  Severe haemophilia A  Randomized study  Prophylaxis 25-35 iu/kg iv x 3/week  Compared to on-demand  Interim analysis shows 93% reduction in

bleeding

 Final report will also address joint damage

and QOL

Manco-Johnson M et al. J Thromb Haemost 2013;11(6):1119-1127

UK tertiary prophylaxis study

 20 men with severe haemophilia A,

aged 30-45 yrs

 6 months on demand compared with 6

months prophylaxis (crossover)

 Median number haemarthroses

reduced from 15 (range 11-26) to 0 (range 0-3).

Collins P. J Thromb Haemost 2010;8:83-89.

UK tertiary prophylaxis study

 On standard prophylaxis median

trough FVIII levels were 6.0 % at 48 hrs and 4% at 72 hrs

 Adults may not need as high doses as

children for prophylaxis

Collins P. J Thromb Haemost 2010;8:83-89.

INHIBITOR PATIENTS

ProFEIBA

 34 boys with severe haemophilia A  Age over 2 yrs  High titre inhibitors  Prospective randomized crossover

study, 6 months on each arm

 FEIBA 85 iu/kg x3/week vs on demand

Leissinger C et al. New Eng J Med 2011;365(18):1684-1692.

ProFEIBA

 62% reduction in all bleeding episodes

(p<0.001)

 61% reduction in haemarthroses

(p<0.001)

 Improved QOL (p<0.05)

Leissinger C et al. New Eng J Med 2011;365(18):1684-1692. Stasyshyn O et al Haemophilia March 2014.

PROOF

 36 people aged 7-56 yrs  Randomized to prophylaxis vs on

demand for 1 yr

 FEIBA 85 iu/kg alternate days

Antunes S et al. Haemophilia 2014;20:65-72.

PROOF

 Annualized bleeding rate 7.9 on

prophylaxis vs 28.7 on demand (p<0.0003)

 3 people (18%) had no bleeds on

prophylaxis

Antunes S et al. Haemophilia 2014;20:65-72.

rVIIa prophylaxis

 3 months on demand vs 3 months

prophylaxis on rVIIa 90 or 270 ug/kg daily

 Statistically significant reduction of

approximately 50% in bleeding seen with both prophylaxis regimens

 Reduced bleeding persisted for 3 months

after prophylaxis stopped.

Konkle B et al. J Thomb Haemost 2007;5(9):1904-1913

Summary

 Primary prophylaxis is the standard of care in

developed countries, reducing bleeding and arthropathy, improving QOL.

 Secondary and tertiary prophylaxis reduce bleeding,

improve QOL and may slow arthropathy

 Prophylaxis in inhibitor patients reduces bleeding

and may improve QOL.

Any questions?