Download - GF2009 Victor S Blanchette
-
8/8/2019 GF2009 Victor S Blanchette
1/23
PROPHYLAXIS:PROPHYLAXIS:THE CANADIAN EXPERIENCETHE CANADIAN EXPERIENCE
Victor S. BlanchetteChief, Division of Hematology/Oncology
The Hospital for Sick ChildrenToronto, Canada
-
8/8/2019 GF2009 Victor S Blanchette
2/23
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
-
8/8/2019 GF2009 Victor S Blanchette
3/23
-
8/8/2019 GF2009 Victor S Blanchette
4/23
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
-
8/8/2019 GF2009 Victor S Blanchette
5/23
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
-
8/8/2019 GF2009 Victor S Blanchette
6/23
Treatment of Breakthrough
Joint Bleeding
Day 1 * 40 Units / kgDay 2 20 Units / kg
Day 4 20 Units / kg
* Day 1 = day of bleed
-
8/8/2019 GF2009 Victor S Blanchette
7/23
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.
-
8/8/2019 GF2009 Victor S Blanchette
8/23
Months Years
MEDIAN 55.5 4.6
RANGE 3 - 120 0.3 - 10
DURATION OF FOLLOW-UP
N=56
-
8/8/2019 GF2009 Victor S Blanchette
9/23
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
*
-
8/8/2019 GF2009 Victor S Blanchette
10/23
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
-
8/8/2019 GF2009 Victor S Blanchette
11/23
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
-
8/8/2019 GF2009 Victor S Blanchette
12/23
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
-
8/8/2019 GF2009 Victor S Blanchette
13/23
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.
-
8/8/2019 GF2009 Victor S Blanchette
14/23
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
-
8/8/2019 GF2009 Victor S Blanchette
15/23
Arrow head ( )represents cartilagethinning
Arrows ( ) represents joint effusion
Arrows ( )represents hemosiderindeposition
MRI study of an ankle jointMRI study of an ankle joint
-
8/8/2019 GF2009 Victor S Blanchette
16/23
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% )
-
8/8/2019 GF2009 Victor S Blanchette
17/23
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.
-
8/8/2019 GF2009 Victor S Blanchette
18/23
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 )
-
8/8/2019 GF2009 Victor S Blanchette
19/23
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 )
-
8/8/2019 GF2009 Victor S Blanchette
20/23
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
-
8/8/2019 GF2009 Victor S Blanchette
21/23
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.
-
8/8/2019 GF2009 Victor S Blanchette
22/23
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.
-
8/8/2019 GF2009 Victor S Blanchette
23/23
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