GF2009 Victor S Blanchette

8/8/2019 GF2009 Victor S Blanchette

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PROPHYLAXIS:PROPHYLAXIS:THE CANADIAN EXPERIENCETHE CANADIAN EXPERIENCE

Victor S. BlanchetteChief, Division of Hematology/Oncology

The Hospital for Sick ChildrenToronto, Canada


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North American Prospective Primary ProphylaxisNorth American Prospective Primary ProphylaxisStudies in Boys with Severe Hemophilia AStudies in Boys with Severe Hemophilia A

Canadian HemophiliaCanadian HemophiliaPrimary Prophylaxis StudyPrimary Prophylaxis Study(1)(1)

( N=56 )*( N=56 )*

USA Joint Outcome StudyUSA Joint Outcome Study(2)(2)

( N=65 )**( N=65 )**

Study designStudy design Single arm, dose-Single arm, dose-escalation studyescalation study

Randomized controlledRandomized controlledtrial: full-dose prophylaxistrial: full-dose prophylaxisvs enhanced episodicvs enhanced episodictherapytherapy

Age ( yr ) at study entryAge ( yr ) at study entry 1 2.51 2.5 < 2.5< 2.5

First index jointFirst index jointhemorrhage beforehemorrhage beforeenrollmentenrollment

45% ( 25/56 )45% ( 25/56 ) 48% ( 31/65 )48% ( 31/65 )

Status of studyStatus of study OngoingOngoing ClosedClosed

* First case enrolled July 1997; ** first case enrolled August 1996(1)

Feldman BM et al J Thromb Haemost 2006; 4: 1228-1236(2) Manco-Johnson MJ et al. N Engl J Med 2007; 357: 535-544


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Study Protocol

50 Units / kg x 1 / week

30 Units / kg x 2 / week

25 Units / kg on alternatedays ( minimum x 3 / week )

STEP 1

STEP 2

STEP 3

Escalation

Escalation


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Escalation Criteria

3 bleeds into any single joint over a consecutive 3 month period

4 significant soft tissue or jointbleeds ( into any number of joints )over a consecutive 3 month period

5 bleeds into any single jointwhile on the same dose of factor therapy


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Treatment of Breakthrough

Joint Bleeding

Day 1 * 40 Units / kgDay 2 20 Units / kg

Day 4 20 Units / kg

* Day 1 = day of bleed


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PARTICIPATING HEMOPHILIAPARTICIPATING HEMOPHILIATREATMENT CENTRES IN CANADATREATMENT CENTRES IN CANADA

Coordinating Centre: The Hospital for Sick Children, Toronto

N= 56Age at Study Entry

Median 1.6 yrs. Range 1-2.5 yrs.


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Months Years

MEDIAN 55.5 4.6

RANGE 3 - 120 0.3 - 10

DURATION OF FOLLOW-UP

N=56


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O u t c o m e o f E s c a la t io n P ro t o

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

O n c e w e e k ly ( S t e p 1 )Tw ic e w e e k ly (S t e p 2 )A lt e rn a t e D a y (S t e p 3 )

F r e q u e n c y o f In

P e r c e

n t a g e In t e r im A n a l ys i s

C u r re n t An a lys is

48%

37.5% 36% 33.9%

16%

28.6%

12/25

21/56

9/25 19/56

4/2516/56

Time to Escalation (Years) to twice weekly infusion (step 2)

Interim CurrentMedian 3.4 3.3

Lower 95% Confidence 2.0 2.0Limit

*Feldman BM et al J Thromb Haemost 2006; 4: 1228-1236

*


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Reasons for Dose EscalationReasons for Dose EscalationSTEP 1 STEP 1 2*2*

( N=35 )( N=35 )STEP 2 STEP 2 33

( N=16 )( N=16 )

3 bleeds into a single joint in3 bleeds into a single joint ina consecutive 3 month perioda consecutive 3 month period

10 ( 29% )10 ( 29% ) 4 ( 25% )4 ( 25% )

4 index joint significant soft4 index joint significant softtissue bleeds in a consecutivetissue bleeds in a consecutive3 month period3 month period

21 ( 60% )21 ( 60% ) 9 ( 56% )9 ( 56% )

5 bleeds into a single index5 bleeds into a single index joint over any period of time joint over any period of timeon studyon study

2 ( 6.7 )2 ( 6.7 ) 3 ( 19% )3 ( 19% )

* 1 protocol violation, 1 intracranial and ankle hemorrhage* 1 protocol violation, 1 intracranial and ankle hemorrhage

Step 1 = once weekly infusions; Step 2 = twice weekly infusions;Step 3 = alternate day infusions


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Physical Examination Joint ScalePhysical Examination Joint Scale (1)(1)

Parameter Parameter ScoreScoreSwellingSwellingRange of motionRange of motionFlexion contractureFlexion contractureMuscle atrophyMuscle atrophy

StrengthStrengthGait *Gait *Axial deformity *Axial deformity *Pain without activityPain without activityPain with activityPain with activity

Use of splints / orthoticsUse of splints / orthotics

0 30 30 30 30 30 30 30 3

0 30 30 20 20 20 20 30 30 30 3

0 30 3

* Knees / ankles only(1) Modified Child Physical Examination (PE) Instrument. Manco-Johnson MJ et al. Joint evaluationinstruments for children and adults with haemophilia. Haemophilia 2000; 6 :649-657

Total Score for all six ( 6 )index joints = 160

2828


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Summary of Joint ScoresSummary of Joint ScoresJoints with No HistoryJoints with No Historyof Bleedingof Bleeding

( N=188)( N=188)

Joints with HistoryJoints with Historyof Bleedingof Bleeding( N=142 )( N=142 )

All JointsAll Joints

( N=330)( N=330)

AnklesAnkles 11( 0 8 )( 0 8 )

11( 0 6 )( 0 6 )

11( 0 8 )( 0 8 )

KneesKnees 00( 0 2 )( 0 2 )

00( 0 6 )( 0 6 )

00( 0 6 )( 0 6 )

ElbowsElbows 00( 0 8 )( 0 8 )

00( 0 8 )( 0 8 )

00( 0 8 )( 0 8 )

Values shown are medians; ( ) = rangesN = number of joints


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Magnetic Resonance Imaging ( MRI )Magnetic Resonance Imaging ( MRI )Scale *Scale *

Progressive ScaleProgressive Scale Additive ScaleAdditive Scale

Soft Tissue ChangesSoft Tissue Changes

- effusions/ hemarthrosis- effusions/ hemarthrosis

- synovial hypertrophy- synovial hypertrophy- hemosiderin- hemosiderin

1 31 3

4 64 64 64 6

Not scoredNot scored

1 31 311

Osteochondral ChangesOsteochondral Changes

- changes of subchondral- changes of subchondral

bone or joint marginsbone or joint margins- cartilage loss- cartilage loss

7 87 8

9 109 10

1 81 8

1 81 8

0 100 10 0 200 20

* Compatible MRI scale developed by the International Prophylaxis Study Group* Compatible MRI scale developed by the International Prophylaxis Study Group( IPSG ) was used for scoring MRIs in this study.( IPSG ) was used for scoring MRIs in this study.


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Frequency of Osteochondral Changes Detected byFrequency of Osteochondral Changes Detected byMRI in 24 Boys on the Canadian PrimaryMRI in 24 Boys on the Canadian PrimaryProphylaxis Study at an Average Age of 8 YearsProphylaxis Study at an Average Age of 8 Years

Number of cases with osteochondral changesNumber of cases with osteochondral changes= 12 / 24 ( 50% )= 12 / 24 ( 50% )

Type of ChangesType of Changes any loss of cartilage heightany loss of cartilage height 22 loss of cartilage height in at least 2 bonesloss of cartilage height in at least 2 bones 22 at least one subchondral cystat least one subchondral cyst 11 surface erosions / multiple subchondral cystssurface erosions / multiple subchondral cysts 11 loss of cartilage height / bony abnormalitiesloss of cartilage height / bony abnormalities 66


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Arrow head ( )represents cartilagethinning

Arrows ( ) represents joint effusion

Arrows ( )represents hemosiderindeposition

MRI study of an ankle jointMRI study of an ankle joint


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Magnetic Resonance Imaging ( MRI ) findings inMagnetic Resonance Imaging ( MRI ) findings inindex joints that did and did not have a history of index joints that did and did not have a history of clinically evident bleedingclinically evident bleeding

Joints with aJoints with aHistory of BleedingHistory of Bleeding

( N=74 )( N=74 )

Joints with NoJoints with NoHistory of BleedingHistory of Bleeding

( N=66 )( N=66 )

Soft Tissue ChangesSoft Tissue Changes

-- any abnormalityany abnormality- synovial hypertrophy- synovial hypertrophy- hemosiderin deposition- hemosiderin deposition

32 ( 43% )32 ( 43% )27 ( 36% )27 ( 36% )27 ( 36% )27 ( 36% )

21 ( 32% )21 ( 32% )17 ( 26% )17 ( 26% )18 ( 27% )18 ( 27% )

Osteochondral changesOsteochondral changes

-- any abnormalityany abnormality- cartilage loss- cartilage loss- subchondral bone changes- subchondral bone changes

13 ( 18% )13 ( 18% )11 ( 15% )11 ( 15% )

7 ( 9% )7 ( 9% )

0 ( 0% )0 ( 0% )0 ( 0% )0 ( 0% )0 ( 0% )0 ( 0% )


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Experience With Central Venous AccessExperience With Central Venous AccessDevices ( Port-A-Catheters )Devices ( Port-A-Catheters )

Number of boys with portsNumber of boys with ports 21 / 56 ( 37.5% )21 / 56 ( 37.5% )

Number of ports removed becauseNumber of ports removed because 9 / 21 ( 43% )9 / 21 ( 43% )they were no longer needed for they were no longer needed for reliable venous accessreliable venous access

Time ports remained inTime ports remained inplace in study cohortplace in study cohort( years )( years )

All CasesAll Cases Cases in whichCases in whichports removedports removed

- median- median- range- range 440.97 10.50.97 10.5 7.47.42.9 10.52.9 10.5

No port related infections were observed; 2 cases had port relatedNo port related infections were observed; 2 cases had port related

thromboses.thromboses.


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CANADIAN DOSE-ESCALATION PRIMARYPROPHYLAXIS STUDY

ProportiononStep1

Proportionon Ste

p1

Median age to escalate fromonce weekly to twice weeklyprophylaxis = 4.1 yrs( 95% CI 2.8-5.9 years )


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Proportionon Step1orStep2

CANADIAN DOSE-ESCALATION PRIMARYPROPHYLAXIS STUDY

Median age to escalate to

full dose (alternate day)prophylaxis = 9.7 yrs

( lower 95% CI 7.6 yrs )


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Effect of Age at First Joint Bleed on the Hazardof Escalating to Twice Weekly ( Step 2 ) or Alternate Day ( Step 3 ) Prophylaxis

n = 56Hazard Ratio

( 95% CI )

P-value

STEP 2 0.71 ( 0.48-1.03 ) 0.07

STEP 3 0.61 ( 0.4-0.94 ) 0.04


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Summary of Key FindingsSummary of Key Findings 50% of boys ( 12/24 ) on the Canadian dose-escalation primary50% of boys ( 12/24 ) on the Canadian dose-escalation primary

prophylaxis regimen have osteochondral changes detectable byprophylaxis regimen have osteochondral changes detectable byMRI at a median age of 8.8 years.MRI at a median age of 8.8 years.

32% of index joints with no history of bleeding have soft tissue32% of index joints with no history of bleeding have soft tissuechanges ( synovial hypotrophy / hemosiderin deposition ) detectablechanges ( synovial hypotrophy / hemosiderin deposition ) detectableby MRI examination at a median age of 8.8 years.by MRI examination at a median age of 8.8 years.

at 10 years from study initiation and after a median follow-up of at 10 years from study initiation and after a median follow-up of 4.6 years ( range4.6 years ( range 0.30.3 toto 1010 ) the median total joint score by physical) the median total joint score by physicalexamination isexamination is 22 ( range( range 00 toto 2121 ).).

the frequency of port-a-catheter use in the study was 37%the frequency of port-a-catheter use in the study was 37%( 21/56 cases ); ports have been electively removed in 9/21( 21/56 cases ); ports have been electively removed in 9/21

( 43% ) of cases. No port related infections have been reported.( 43% ) of cases. No port related infections have been reported.


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ConclusionsConclusions Although the frequency of early osteochondral changesAlthough the frequency of early osteochondral changes

detected by MRI are higher in the Canadian dose-escalationdetected by MRI are higher in the Canadian dose-escalationstudy as compared to the USA Joint Outcome Study ( 50% vsstudy as compared to the USA Joint Outcome Study ( 50% vs7% ) the long-term functional significance of these findings7% ) the long-term functional significance of these findingsremains unclear. Continued follow-up of the Canadian cohortremains unclear. Continued follow-up of the Canadian cohortis warranted.is warranted.

Reasons for failure of primary prophylaxis regimens areReasons for failure of primary prophylaxis regimens aremultiple and include non-compliance with the prophylaxismultiple and include non-compliance with the prophylaxisregimen, different activity profiles between subjects andregimen, different activity profiles between subjects andindividual pharmacokinetics of infused FVIII. Future studiesindividual pharmacokinetics of infused FVIII. Future studiesto more clearly examine these variables on the outcome of to more clearly examine these variables on the outcome of primary prophylaxis regimens are needed.primary prophylaxis regimens are needed.


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Amanda NgJennifer AikenheadBetty HaleKathy Mulder

Donna LangenHeather Zucker Pam HilliardBrenda ElliotNick ZourikianGaetan Thibault

Bethany LezamaCarolyn JarockHeather SecordJulia BrooksLori EnnsMatthew ThiessenKaren StrikeCatherine Van NesteJoAnn Nilson

John WuMan-Chiu PoonJohn AkabutuSara Israels

Mohan PaiAnthony ChanVictor BlanchetteDavid LillicrapBrian LukeRobert Klaassen

Georges RivardChristine DemersDorothy BarnardSue RobinsonVictoria PriceManuel CarcaoNicole LaferriereRobert CardMacGregor Steele

Morna BrownPat KleinAndrea PritchardNora Schwetz

Rose JacobsonCarol EdwardsJulia SekAnn Marie StainGeorgina FlorosDiane Bissonnette

Claudine AmesseGinette LupienSue Ann HawesLynne PayneAlice LautChelsie Fraser Erica PurvesKay Decker Wendy SeroskiMarian EbyKaren RobertsHelene NeronDianne Dufour

THANKS TEAM CANADA !THANKS TEAM CANADA !THANKS TEAM CANADA !THANKS TEAM CANADA !

Funding for this study was provided by the Medical Research Councilof Canada / PMAC ( Industry Partner Bayer, Inc. ), the Bayer/Canadian

Blood Services Hema-Quebec Partnership Fund and Bayer HealthCare Pharmaceuticals

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GF2009 Victor S Blanchette