Victor S. Blanchette, MD, FRCP. Manuel D. Carcao, MD, MSc. Amy D. Shapiro, MD

Transcription

1

2 Victor S. Blanchette, MD, FRCP Manuel D. Carcao, MD, MSc Amy D. Shapiro, MD

3 Disclosure Information The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Name of Faculty or Presenter Reported Financial i Relationship Victor S. Blanchette, MD, FRCP Consulting/Speaker Fees: Baxter, Bayer HealthCare Pharmaceuticals, Novo Nordisk Inc., Octapharma, Wyeth Pharmaceuticals (Pfizer Inc.) Manuel D. Carcao, MD, MSc Consulting/Speaker Fees: Baxter, CSL Behring, Novo Nordisk Inc., Wyeth Pharmaceuticals (Pfizer Inc.) Amy D. Shapiro, MD Consulting Fees: All fees given to parent institution; Contracted Research: Clinical research protocols. All fees given to parent institution The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Name of Planner or Manager Reported Financial Relationship PIM Clinical Reviewers: Trace Hutchison, PharmD; Jan Hixon, RN, BSN, MA; Linda Graham, RN, BSN, BA; Jan Schultz, RN, MSN, CCMEP; Julia Kirkwood, RN, BSN ECM: Patrick J. Crowley, Senior Director of Operations; Jodi Andrews, Foundation Manager; Gay Boyle, Editorial Services Have no real or apparent conflicts of interest to report. Have no real or apparent conflicts of interest to report. 3

4 Learning Objectives Upon completion of this activity, participants should be better able to: Discuss the role of patient and environmental risk factors in the development of inhibitors in hemophilia Describe the clinical consequences of inhibitors, including joint disease and arthropathy Assess current studies that examine the role of bypassing agents as on-demand and prophylactic therapy in patients with hemophilia and inhibitors Compare dosing strategies for the prophylactic administration of bypassing agents to treat hemophilia patients with inhibitors Outline the rationale for administering prophylactic therapy during ITI 4

5 Introduction and Background to Inhibitor Development Victor S. Blanchette, MD, FRCP Head, Division of Hematology/Oncology Hospital for Sick Children Professor, Department of Pediatrics University of Toronto Toronto, Ontario, Canada

6 ARS Polling Question In your practice, how many hemophilia patients with inhibitors are you currently treating? a) 0 b) 1-2 c) 3-4 d) 5 6

7

8 Inhibitors: An Overview Inhibitors represent the most serious and challenging complication affecting patients t with hemophilia hili today 1 Resistance to conventional clotting factor replacement therapy 2 Inhibitor development occurs primarily during early childhood 3,4 Median age years Median of 9-12 days of factor exposure Prior to 200 factor-exposure days 1. Franchini M, et al. Haemophilia. 2009;15: ; 2. Croom KF, et al. Biodrugs. 2008;22: ; DiMichele DM. Int J Hematol. 2006;83: ; Bray GL, et al. Blood. 1994;83:

9 Incidence and Detection of Inhibitors Estimated worldwide incidence of inhibitors in patients with severe (<1% FVIII) hemophilia A is 20%-33% 1 Incidence of inhibitors in patients with severe hemophilia B is 1%-6% 1 Bethesda assay used to confirm presence of inhibitors 1 Nijmegen modification more sensitive for lower-titer inhibitor 2 1. DiMichele DM. Inhibitors in Hemophilia: A Primer. 4th ed. World Federation of Hemophilia. April Available at: Accessed February 24, 2010; 2. Verbruggen B, et al. Thromb Haemost. 1995;73:

10 Definitions Type of Antibody Neutralizing High Titer* Low Titer Non-neutralizing Definition Antibodies that inhibit the function of coagulation factors 5 Bethesda Units (BU) <5 Bethesda Units (BU) Antibodies that do not inhibit the function of coagulation in factors *Patients do not respond to infused FVIII/FIX. Treatment with bypassing agents required. 9

11 Traditional Model of Hemostasis Intrinsic Pathway factor XII HMK PK BYPASSING AGENTS Activated prothrombin complex concentrates; apccs eg FEIBA Recombinant factor FVIIa; rfviia Extrinsic Pathway factor XI factor IX factor XIa factor IXa factor VIIIa PL, Ca +2 factor VIIa tissue factor PL, Ca +2 factor X factor Xa factor Va PL, Ca +2 factor X Prothrombin II Thrombin IIa fibrinogen fibrin PL Phospholipid Adapted from Hoffman M, et al. Thromb Haemost. 2001;85:

12 Factor VIII Immune Response CD 40 CD 40L CD 4 + T Cell MHC Class II TCR Antigen-Presenting Cell (APC) CD 80/86 CD 28 Activated T Cell FVIII Peptide B Cell Memory B Cell Plasma Cell Anti-Factor VIII Antibodies 11

13 Factors Influencing Inhibitor Development and Detection Host ( Patient )-related factors Type of hemophilia (VIII vs IX) Severity of hemophilia (severe > moderate > mild) Family history of inhibitors Type of genetic mutations (especially large gene deletions, nonsense mutations and intron 1 and 22 inversions) Ethnic origin (eg, African and Hispanic heritage) Immune response factors (eg HLA type, IL-10 polymorphisms) Astermark J. Semin Hematol. 2006;43(suppl 4):S3-S7; DiMichele DM. Int J Hematol. 2006;83: ; Reding MT. Haemophilia. 2006;12(suppl 6):

14 Factors Influencing Inhibitor Development and Detection (cont) Extrinsic ( Therapy-Related ) factors Type of factor concentrates Intensity of treatment (surgery, treatment for >5 consecutive days) Context in which factor concentrates are administered ( danger signals ) Assay-related factors Sensitivity and specificity of inhibitor assay Frequency of inhibitor testing DiMichele DM. Int J Hematol. 2006;83: ; Reding MT. Haemophilia. 2006;12(suppl 6):30-36; Verbruggen B, et al. Thromb Haemost. 1995;73:

15 Risk Factors for Inhibitor Development in Hemophilia A High Risk 75% multi domain Large 5.1 Deletions Bonn Hemophilia Center n = 107 = Relative risk of inhibitor development light chain 2.3 Nonsense Mutations single domain heavy chain Intron 22 Inversions % Low Risk Adapted from Oldenburg J, et al. Haematologica. 2000;85(10 suppl):7-14. Non A-run C1-C2-junction Small Missense Deletions Mutations Non C1-C2-junction Splice Site A-run Mutations 14

16 Definitions Prevalence Proportion of a patient population with inhibitors at a given time Incidence Number of new inhibitor cases in a defined d period of time Cumulative incidence Number of new inhibitor cases over a prolonged period adjusted for the different length of follow-up of different patients Wight J, et al. Haemophilia. 2003;9:

17 Recombinant FVIII Studies in Previously Unrelated Patients (PUPs) With Hemophilia A: Incidence of Inhibitors Study No. of Evaluable Cases No. With Inhibitors Percent With High Titre Inhibitors ( 10 BU) Study Duration (Months) Lusher et al (19.8) 44 (7/16) 42 Bray et al (3.9) 41.2 (7/17) 33 Rothschild et al (28) 28.6 (4/14) 74 Courter et al (34.8) 37.5 (12/32) (26.9) 37.9 (30/79) 1. Lusher J, et al. N Engl J Med. 1993;328: ; 2. Bray G, et al. Blood. 1994;83: ; 3. Rothschild C, et al. Thromb Haemost. 1998;80: ; 4. Courter S, et al. Sem Hematol. 2001;38(suppl 4):

18 Study Conclusions The higher incidence of inhibitors in recombinant PUPs studies likely l reflects the fact that: t The studies were prospective* (ie, true incidence ce vs prevalence e studies) Frequency of inhibitor testing was generally every 3 months (minimum every 6 months )* Patients studied were the most at-risk group (ie, severe cases) *Factors that facilitate the detection of low-titer/transient inhibitors. 17

19 The CANAL Cohort Study Recombinant vs plasma-derived FVIII products and the development of inhibitors in PUPs with severe hemophilia A Number of evaluable cases: 316 Number of inhibitor-positive cases: 82 (26%) High titer 66* (20.8%) Low titer 16 (5.1%) * >5 BU. Gouw S, et al, for the CANAL Study group. Blood. 2007;109:

20 CANAL Study: Results The risk of developing an inhibitor was similar for Recombinant vs plasma-derived products (RR 0.8; 95% CI ) Recombinant vs plasma-derived products containing considerable quantities of vwf [>0.01 IU vwf/iu FVIII] (RR 1.0; 95% CI ) The risk of developing an inhibitor was not increased after switching to another FVIII product (RR 0.9; 95% CI ) Gouw S, et al, for the CANAL Study Group. Blood. 2007;109:

21 Clinical Consequences of Inhibitors Inhibitor patients experience hemorrhagic episodes that are less well controlled compared to non-inhibitor patients Increased incidence of target joint development Common bleeding sites: Knee: 45% Elbow: 30% Ankle: 15% Shoulder: 3% Wrist: 3% Hip: 2% Other: 2% World Federation of Hemophilia. Guidelines for the Management of Hemophilia. Available at: Accessed September 17,

22 Pathophysiology of Hemophilic Arthropathy 21

23 Joint Disease and Arthropathy Inhibitor patients at greater risk of developing arthropathy and orthopedic complications than non-inhibitor patients 1 Reduced mobility 1 2-fold greater loss of joint ROM versus patients with undetectable inhibitor levels 2 1. Croom KF, et al. Biodrugs. 2008;22: ; 2. Leissinger CA. Haemophilia. 2006;12(suppl 6):

24 Late Hemophilic Arthropathy Natural history of hemophilic synovitis is progression to end-stage arthropathy Fibrous tissue Contractures Fibrous ankylosis Progressive muscle atrophy Joint subluxation Large periarticular synovial cysts in adjacent bone Shapiro AD, et al. The role of prophylaxis in managing hemophilia in adult and pediatric populations. Available at: Accessed September 17,

25 Factor VIII Inhibitors in Mild and Moderate Hemophilia A Inhibitors typically develop following intensive replacement therapy Types of inhibitors Inhibitor recognizes both native and exogenous FVIII converted to severe hemophilia Inhibitor recognizes only exogenous FVIII Bleeding gpattern is similar in many cases to that seen in patients with acquired hemophilia Extensive bleeding into soft tissues/muscles (bleeding into joints relatively e uncommon) o Bleeding from mucosal sites (eg, gross hematuria) Response to ITI not as good as that seen in subjects with severe hemophilia hili and high-titer h i inhibitors Hay CRM, et al. Thromb Haemost. 1998;79:

26 Key Questions Regarding Inhibitor Development and Management in the Hemophilia Population Is the incidence of inhibitors in at-risk patients higher for recombinant vs plasma-derived FVIII/vWF-containing concentrates? What is the optimal immune tolerance induction (ITI) protocol for use in subjects with newly diagnosed high-titer inhibitors to FVIII? What is the role of prophylaxis treatment using bypassing agents in patients who are receiving ITI or who have failed ITI regimens? 25

27 Management of High-Titer FVIII Inhibitors Manuel D. Carcao, MD, MSc Division of Haematology/Oncology Hospital for Sick Children Associate Professor Department of Paediatrics University of Toronto Toronto, Ontario, Canada

28 ARS Polling Question What are the major barriers to the use of bypassing agents as prophylactic therapy for hemophilia patients with inhibitors? a) Cost b) Clinician acceptance of the therapeutic regimen c) Unsure of appropriate product choice and dosing strategy d) CVAD issues e) Patient acceptance of the therapeutic regimen f) All of the above 28

29

30 Impact of Inhibitors Inhibitor patients have: More difficult to treat bleeds Worse joint disease susceptibility to lifethreatening bleeds (eg, ICH) Worse quality of life (QoL) More absences from school/work hospitalization

31 Impact of Inhibitors Inhibitor patients have: More difficult to treat bleeds Worse joint disease susceptibility to lifethreatening bleeds (eg, ICH) Worse quality of life (QoL) More absences from school/work hospitalization Patients are complex and should be managed by an expert hemophilia team

32 What to Do When a High-Titer Inhibitor Develops 1. Stop further FVIII exposure 2. Treat bleeds using bypassing agents: apccs rfviia 3. Usually need CVL 4. Start ITI 5. Consider prophylaxis with bypassing agents 30

33 What to Do When a High-Titer Inhibitor Develops 1. Stop further FVIII exposure 2. Treat bleeds using bypassing agents: apccs rfviia 3. Usually need CVL Focus on these 4. Start ITI 5. Consider prophylaxis with bypassing agents 30

34 Factor Choices for Patients With Inhibitors rfviia Recombinant Very low volume (2 cc/infusion) Push over 1-2 min Short half-life (2-3 hr) Very low risk of thrombosis apcc=activated prothrombin complex concentrates; rfviia=recombinant factor VIIa. apcc Plasma-derived Mixture of activated FII, VII, IX, and X Possible anamnesis residual FVIII Larger volume 1000 U/10 cc Administer over minimum 15 min Longer half-life (4-7 hr) Very low risk of thrombosis Berntorp E. Haemophilia. 2009;15:3-10; Croom KF, et al. Biodrugs. 2008;22: ; DiMichele DM. Int J Hematol. 2006;83: ; Lyseng-Williamson KA, et al. Pharmacoeconomics. 2007;25: ; Negrier VK, et al. J Thromb Haemost. 2003;1:

35 Variables Influencing Treatment Choice Inhibitor state e.g. Pre-ITI favor rfviia due to potential for anamnesis with apccs Patient age and venous access Easier to push something over 1-2 min rather than infuse over 15 min Historical response to treatment Patient choice Bleed type Some bleeds might respond better to one agent than to another Time from bleed to start of treatment Cost One agent may be better for early treatment and other for late treatment DiMichele DM. Int J Hematol. 2006;83: ; National Hemophilia Foundation. MASAC Document No Available at: Accessed March 16,

36 Treatment t of Bleeds in Patients with Inhibitors What is clinical experience with p the two bypassing agents?

37 apccs vs rfviia in Treating Bleeds Many studies show that both agents work most of the time Either agent acceptable 1 Inter-patient and intra-patient variability in response to bypassing agents 1 If bleeds do not respond to one agent switch to other 1 Rarely may have to use both sequentially virtually never together 2 1. Haya S, et al. Haemophilia. 2007;13(suppl 5):52-60; 2. Gomperts ED, et al. Blood Rev. 2008;22(suppl 1):S1-S11. 34

38 Comparative Studies: FENOC Study Few comparative trials of apccs and rfviia as on-demand treatment of bleeds FEIBA NovoSeven Comparative (FENOC) Study evaluated both agents in the treatment of bleeds in hemophilia A patients with inhibitors Prospective, open-label, randomized, crossover design Equivalence of FEIBA and rfviia tested: degree to which they yp provided the same, or nearly the same, clinical efficacy Astermark J, et al, for the FENOC Study Group. Blood. 2007;109:

39 FENOC Study (cont) Study results FEIBA and rfviia appeared to exhibit similar hemostatic effectiveness Many patients rated one or the other product as superior Rates of efficacy* by treatment and time point Hrs after % effectiveness P infusion, N FEIBA rfviia (75 U/kg) (90 ug/kg X 3) 2 (48) (47) (45) (42) (41) (41) *Efficacy defined d as effective or partially effective by patient rating. Prior to second dose of rfviia. Astermark J, et al, for the FENOC Study Group. Blood. 2007;109:

40 FENOC Study (cont) Study results FEIBA and rfviia appeared to exhibit similar hemostatic effectiveness Many patients rated one or the other product as superior Rates of efficacy* by treatment and time point Hrs after % effectiveness P infusion, N FEIBA rfviia (75 U/kg) (90 ug/kg X 3) 2 (48) (47) (45) (42) (41) Study failed to show equivalence, but close! 48 (41) *Efficacy defined d as effective or partially effective by patient rating. Prior to second dose of rfviia. Astermark J, et al, for the FENOC Study Group. Blood. 2007;109:

41 rfviia: 90 ug/kg X 3 doses vs. 270 ug/kg g X 1 dose Kavakli et al (2006) evaluated efficacy and safety of rfviia in treating jt bleeds (randomized double blind cross-over over study) 90 µg kg -1 at Hr 0, 3 and µg kg -1 X 1 dose at Hr 0 followed by placebo at Hr 3 and 6 Administered at Home within 1 hr of recognition of a bleed Effectiveness of therapy assessed using a new Global Assessment Response Scoring System Patient self-assessment of changes in joint pain/mobility At 1, 3, 6 and 9 hrs following initiation of treatment of a joint bleed Posted with permission from Kavakli K, Makris M, Zulfikar B, et al. Home treatment of haemoarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. Thromb Haemost. 2006;95:

42 rfviia: 90 ug/kg X 3 doses vs. 270 ug/kg g X 1 dose Kavakli et al (2006) evaluated efficacy and safety of rfviia in treating jt bleeds (randomized double blind cross-over over study) 90 µg kg -1 at Hr 0, 3 and µg kg -1 X 1 dose at Hr 0 followed by placebo at Hr 3 and 6 1) 90 ug/kg X 3 1)270 ug/kg X 1 2)270 ug/kg X 1 N=11 pts 2) 90 ug/kg X 3 N=10 pts Total N=21 pts Mean age 27 (6-60) 90 ug/kg X 3 7 / 11 7 / 9 14 / 20 % effective (64%) (78%) (70%) 270 ug/kg X 1 6 / 10 7 / / 20 % effective (60%) (70%) (65%) Posted with permission from Kavakli K, Makris M, Zulfikar B, et al. Home treatment of haemoarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. Thromb Haemost. 2006;95:

43 rfviia: 90 ug/kg X 3 doses vs. 270 ug/kg g X 1 dose Kavakli et al (2006) evaluated efficacy and safety of rfviia in treating jt bleeds (randomized double blind cross-over over study) 90 µg kg -1 at Hr 0, 3 and µg kg -1 X 1 dose at Hr 0 followed by placebo at Hr 3 and 6 No difference in effectiveness of the Total 2 regimens 1) 90 ug/kg X 3 1)270 ug/kg X 1 N=21 pts 2)270 ug/kg g X 1 N=11 pts 2) 90 ug/kg g X 3 N=10 pts i.e. 270 ug/kg X 1 just as effective as 90 ug/kg X 3 Mean age 27 (6-60) 90 ug/kg X 3 7 / 11 7 / 9 14 / 20 % effective (64%) (78%) (70%) 270 ug/kg X 1 6 / 10 7 / / 20 % effective (60%) (70%) (65%) Posted with permission from Kavakli K, Makris M, Zulfikar B, et al. Home treatment of haemoarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. Thromb Haemost. 2006;95:

44 rfviia: 90 ug/kg X 3 doses vs. 270 ug/kg X 1 dose vs. FEIBA 75 U/kg Young et al (2008): Randomized double blind cross-over study rfviia: 90 ug/kg g/ g at Hr 0,, 3 and 6 ( (blinded) ) rfviia: 270 ug/kg at Hr 0 then placebo at Hr 3 and 6 (blinded) apcc 75 U/kg at Hr 0 (not blinded) Global Assessment Response Scoring System 22 pts received all 3 regimens i Mean age 19 yr Range: yr Posted with permission from Young G, et al. Haemophilia. 2008;14: Copyright by Wiley-Blackwell. 39

45 rfviia: 90 ug/kg X 3 doses vs. 270 ug/kg X 1 dose vs. FEIBA 75 U/kg Young et al (2008): Randomized double blind cross-over study of rfviia: 90 ug/kg g/ g at Hr 0,, 3 and 6 ( (blinded) ) rfviia: 270 ug/kg at Hr 0 then placebo at Hr 3 and 6 (blinded) apcc 75 U/kg at Hr 0 (not blinded) Global Assessment Response Scoring System No statistically significant i ifi t difference between regimens but trend towards rfviia being more effective Posted with permission from Young G, et al. Haemophilia. 2008;14: Copyright by Wiley-Blackwell. 39

46 rfviia: 90 ug/kg X 3 doses vs. 270 ug/kg X 1 dose vs. FEIBA 75 U/kg Young et al (2008): Randomized double blind cross-over study of rfviia: 90 ug/kg g/ g at Hr 0,, 3 and 6 ( (blinded) ) rfviia: 270 ug/kg at Hr 0 then placebo at Hr 3 and 6 (blinded) apcc 75 U/kg at Hr 0 (not blinded) Caution C ti in i interpretation i tglobal assessment t ti response off findings fi di scoring system given that the apcc regimen was not No statistically blinded 22 pts significant i ifi t difference between regimens but trend may y have influenced patient p and treater towards rfviia perception of response to therapybeing more effective received all 3 This regimens Posted with permission from Young G, et al. Haemophilia. 2008;14: Copyright by Wiley-Blackwell. 39

47 Home Treatment For greater effectiveness, bleeds should be treated at home (as quickly as possible)

48 Home Therapy With Bypassing Agents Home therapy with coagulation factors well established in noninhibitor hemophilia A or B Benefits of home therapy Reduced time between bleed and treatment More rapid resolution of bleed Better preservation of joint function Improved patient QoL Home therapy in inhibitor patients with bypassing agents not as well established but certainly possible Holme PA, et al. Haemophilia. 2009;15:

49 Prophylaxis in Inhibitor Patients What is the clinical experience with p the two bypassing agents?

50 Use of Prophylaxis in Hemophilia A Patients With Inhibitors Prophylaxis now =standard of care in noninhibitor patients with severe disease frequency of joint and other bleeds Prevention of joint damage Until recently Prophylaxis rarely undertaken in inhibitor patients Prophylaxis in inhibitor patients is challenging g Unpredictable hemostatic effects No laboratory assays to guide dosing Need for very frequent dosing Costly Fischer K, et al. Haemophilia. 2008;14(suppl 3): ; Kempton CL, et al. Blood. 2009;113:11-17; Leissinger CA. Haemophilia. 2006;12(suppl 6):67-73 ; Manco-Johnson MJ, et al. N Engl J Med. 2007;357: ; National Hemophilia Foundation. Recommendations, No November 4,

51 What Is the Clinical Experience With Bypassing Agents for Prophylaxis? apccs Case reports Case series Meta-analysis rfviia Case reports Case series Meta-analysis & randomized study

52 Meta-analysis of FEIBA Prophylaxis: Valentino et al (2010) 6 studies reviewed Hilgartner et al 2003 Valentino et al 2004 Cheng et al 2006 Lambert et al 2006 Ewing et al 2007 Leissinger et al 2007 Valentino LA. Haemophilia. 2010;16:

53 Meta-analysis of FEIBA Prophylaxis: Valentino et al (2010) 6 studies reviewed N=33 inhibitor pts Mean age 10.1 yr (range: 3-39 yr) Mainly children and young adults Valentino LA. Haemophilia. 2010;16:

54 Meta-analysis of FEIBA Prophylaxis: Valentino et al (2010) 6 studies reviewed N=33 inhibitor pts Mean age 10.1 yr (range: 3-39 yr) Mean duration of FEIBA prophylaxis 2.3 yr (range: yr) Mean FEIBA dose 78.5 U/kg (range: U/kg) Mean freq. of infusions: 3-4x/wk Valentino LA. Haemophilia. 2010;16:

55 Meta-analysis of FEIBA Prophylaxis: Valentino et al (2010) 6 studies reviewed N=33 inhibitor pts Mean age 10.1 yr (range: 3-39 yr) Mean duration of FEIBA prophylaxis 2.3 yr (range: yr) Mean FEIBA dose 78.5 U/kg (range: U/kg) Mean freq. of infusions: 3-4x/wk Various regimens used Valentino LA. Haemophilia. 2010;16:

56 Overall Findings: Bleed Prevention 31/33 pts (94%) experienced a reduction in joint bleeds (and other bleeds) nt of hemorr bleed ds rrhages / yr Mean reduction in joint bleeding: 74% 10 # Number of joi P< On-demand Prophylaxis Valentino LA. Haemophilia. 2010;16: Treatment period 49

57 rfviia Prophylaxis Study: Konkle et al (2007) Randomized trial evaluating safety and efficacy of prophylactic rfviia in reducing bleed frequency in highly bleeding inhibitors patients 22 patients with severe hemophilia Randomized to receive rfviia either 90 µg/kg/day 270 µg/kg/day Konkle BA, et al. J Thromb Haemost. 2007;5:

58 rfviia Prophylaxis Study: Konkle et al (2007) Mea an # of bleeds/m month % % 90 ug/kg/day 270 ug/kg/day 0 Pre-Prophylaxis Prophylaxis Post-Prophylaxis

59 rfviia Prophylaxis Study: Konkle et al (2007) Mea an # of bleeds/m month ug/kg/day 270 ug/kg/day -45% Findings: Clinically relevant reductions in bleeding frequency were observed -59% with both rfviia prophylaxis regimens Pre-Prophylaxis Prophylaxis Post-Prophylaxis

60 Overall Conclusions Regarding Management of Inhibitor Patients Role for both agents (rfviia and apcc) in: Treatment of bleeds Both agents work most of the time Both less effective than conventional factor in noninhibitor patients Some patients find one or the other better Prophylaxis Both seem to reduce bleeding frequency Both less convenient than conventional factor in noninhibitor patients Both more costly than conventional factor in noninhibitor patients Many questions remain In which patients should prophylaxis be initiated? When should it be started? When do you stop prophylaxis? Which regimens should be used? 52

61 Overall Conclusions Regarding Management of Inhibitor Patients Role for both agents (rfviia and apcc) in: Treatment of bleeds Both agents work most of the time Both less effective than conventional factor in noninhibitor patients Some patients find one or the other better Prophylaxis Both seem to reduce bleeding frequency Both less convenient than conventional factor in noninhibitor patients Both more costly than conventional factor in noninhibitor patients Many questions remain In which patients should prophylaxis be initiated? When should it be started? When do you stop prophylaxis? Which regimens should be used? No head-to-head comparison between agents for prophylaxis 52

62 Overall Conclusions Regarding Management of Inhibitor Patients Role for both agents (rfviia and apcc) in: Treatment of bleeds Both agents work most of the time Both less effective than conventional factor in noninhibitor patients Some patients find one or the other better Prophylaxis Both seem to reduce bleeding frequency Both less convenient than conventional factor in noninhibitor patients Both more costly than conventional factor in noninhibitor patients Many questions remain In which patients should prophylaxis be initiated? When should it be started? When do you stop prophylaxis? Which regimens should be used? No head-to-head comparison between agents for prophylaxis 52

63 Overall Conclusions Regarding Management of Inhibitor Patients Role for both agents (rfviia and apcc) in: Treatment of bleeds Both agents work most of the time Both less effective than conventional factor in noninhibitor patients Some patients find one or the other better Prophylaxis Both seem to reduce bleeding frequency Both less convenient than conventional factor in noninhibitor patients Both more costly than conventional factor in noninhibitor patients Many questions remain In which patients should prophylaxis be initiated? When should it be started? When do you stop prophylaxis? Which regimens should be used? No head-to-head comparison between agents for prophylaxis 52

64 Overall Conclusions Regarding Management of Inhibitor Patients Role for both agents (rfviia and apcc) in: Treatment of bleeds Both agents work most of the time Both less effective than conventional factor in noninhibitor patients Some patients find one or the other better It is still better not to have an inhibitor Immune Tolerance Induction Therapy (ITI) Prophylaxis Both seem to reduce bleeding frequency Both less convenient than conventional factor in noninhibitor patients Both more costly than conventional factor in noninhibitor patients Many questions remain In which patients should prophylaxis be initiated? When should it be started? When do you stop prophylaxis? Which regimens should be used? No head-to-head comparison between agents for prophylaxis 52

65 ITI and Management of Inhibitors in Patients With Severe Hemophilia A or B Amy D. Shapiro, MD Medical Director Indiana Hemophilia and Thrombosis Center Indianapolis, Indiana Adjunct Professor of Pediatrics Michigan State University East Lansing, Michigan

66 ARS Polling Question Which of the following is a characteristic of a hemophilic patient with inhibitors who would be a good risk for immune tolerance induction (ITI)? a) Peak historical i titer >200 BU b) Pre-ITI titer <10 BU c) >5 years since inhibitor diagnosis 57

67

68 Predictors of ITI Success Putative predictors of ITI success Historical peak titer 82% successful for titer <50 BU Increase in historical titer decrease in rate of success 1,2 Titer at time of ITI initiation 1 Titer <10 BU immediately before start of ITI positively affected likelihood of success and the time required to achieve tolerance Time from inhibitor development e e to start t of ITI <5 years more favorable outcome >5 years less favorable outcome 1. Kroner BL. Vox Sang. 1999;77(suppl 1):33-37; 2. Lenk H. Haematologica. 2000;85:

69 Inhibitor Risk Categories for ITI Good risk ITI patients Peak historical titer <200 BU Pre-ITI titer <10 BU* <5 years since diagnosis of inhibitor Poor risk ITI patients Peak historical i titer >200 BU Pre-ITI titer >10 BU* >5 years since inhibitor diagnosis *Analysis based on immune tolerance registry data; international workshop on ITI. DiMichele DM, et al. Haemophilia. 2007;13(suppl 1):

70 Product Choice for ITI High success rates reported with both monoclonal antibody purified FVIII and recombinant FVIII Debate regarding use of vwf containing FVIII concentrate as a superior product for ITI German and French data 1,2 No prospective randomized data exists: RESIST trial 1. Auerswald G, et al. Haematologica. 2003;88:EREPO5; 2. Orsini F, et al. Haematologica. 2005;90:

71 Clinical Recommendations: Grading and Levels of Evidence for ITI Grade Level Evidence A Ia Meta-analysis of randomized controlled trials (RCT) A Ib At least one RCT B IIa At least one well-designed, controlled study without randomization B IIb At least one other type of well-designed, d quasi-experimental i study B III Well-designed, non-experimental, descriptive studies (e.g. comparative, correlational, case control studies) C IV Expert committee reports or opinions and/or clinical evidence by respected authorities Agency for Health Care Policy and Research AHCPR publication ; DiMichele DM, et al. Haemophilia. 2007;13(suppl 1):

72 Consensus Recommendations: Dosing in ITI 1. ITI is successful using FVIII products with and without vwf (level IIb) 2. No data support the superiority of any FVIII product (level IIb) 3. Most patients are tolerized with the same FVIII product used at time of inhibitor detection. This approach works and there is no evidence to support switching to another FVIII product for de novo ITI (level IIb) DiMichele DM, et al. Haemophilia. 2007;13(suppl 1):

73 Consensus Recommendations: Prophylaxis During ITI 1. Prophylaxis should be considered in patients with frequent bleeding while awaiting or on ITI (level III) 2. rfviia dose µg/kg/day is preferred for prophylaxis when ITI delayed to achieve titer <10 BU (level IV) 3. Prophylaxis with FEIBA U/kg/day to twice weekly or rfviia µg/kg/day may be considered for patients on ITI who experience early joint bleeding or ICH (level III) 4. Monitor FVIII recovery when inhibitor titer drops to 10 BU (level IV) 5. Discontinue bypassing therapy at any level of FVIII recovery (level IV) DiMichele DM, et al. Haemophilia. 2007;13(suppl 1):

74 Venous Access in ITI and Prophylaxis Important issue - yet options available Peripheral veins is preferred option Central venous access devices, CVADs Blanchette VS, et al. Blood Coagul Fibrinolysis. 1997;8(suppl 1):S11-S14; Mancuso ME, et al. Haematologica. 2009;94: ; Santagostino E, et al. Blood Transfus. 2008;6(suppl 2):S12-S16. 64

75 Types of Venous Access in Hemophilic Children: Pros and Cons Adapted from Santagostino E, et al. Blood Transfus. 2008;6(suppl 2):S12-S16. 65

76 ITI Success Rate in Hemophilia A 60%-80% hemophilia A 29% failure rate Tolerance can be achieved in 1-3 years Risk of relapse after 15 years, 15% Mathew P. Semin Hematol. 2006;43(suppl 4):S8-S13. 66

77 FIX Inhibitors: Special Issues What is different about FIX inhibitors and why? Generally high responding: 80% FVIII inhibitors bto 50% Associated with severe infusion reactions Poorer outcome with immune tolerance Development of nephrotic syndrome with immune tolerance Chitlur M, et al. Haemophilia. 2009;15: ; Tjønnfjord GE, et al. Vasc Health Risk Manag. 2007;3:

78 FIX Inhibitors and ITI Modalities employed Factor IX alone, FIX & immune globulin, FIX & plasmapheresis Malmö protocol Rituximab ITI in FIX inhibitors Registry data ITI attempted 39/94: 42% ITI successful 5/39: 13% Desensitization prior to start of ITI if reactions experienced Consider pretreatment with steroids, diphenhydramine to control reaction during ITI if persistent Reactions may reemerge during ITI Associated with increase in inhibitor titer Associated with nephrosis 13/39: 33% DiMichele DM. Thromb Haemost. 2002;87:52-57; Dioun AF, et al. J Allergy Clin Immunol. 1998;102: ; Warrier I, et al. J Pediatr Hematol Oncol. 1997;19: Chitlur M et al. Haemophilia 2009;15:

79 Summary and Future Directions Victor S. Blanchette, MD, FRCP Head, Division of Hematology/Oncology Hospital for Sick Children Professor, Department of Pediatrics University of Toronto Toronto, Ontario, Canada

80 Summary Patient and environmental factors are potential contributors to inhibitor development Inhibitor patients are at increased risk for musculoskeletal complications and joint disease compared to non-inhibitor patients t Because of variability in hemostatic response to bypassing agents, bypassing therapy should be customized for each patient Studies suggest that bypassing agents are safe and effective as prophylactic treatment in patients with hemophilia and inhibitors Inhibitor eradication improves outcome and should be the goal for patients with high titer inhibitors 70

81 Emerging Therapies for Inhibitor Management Recombinant porcine FVIII (phase II trials completed) 1 Long-acting rfviia (phase I trials) 2 Rituximab, CD20 antibody treatment 3 Experimental approaches such as oral tolerance or peptide therapy may hold promise 3 1. National Institutes of Health. Study of Recombinant Porcine Factor VIII (FVIII) in Hemophilia and Inhibitors to FVIII. ClinicalTrials.gov. Available at: Accessed February 24, 2010; 2. National Hemophilia Foundation. Novo Nordisk Starts Clinical Trials of Long-Acting Factor VIIa Product. Available at: Accessed February 24, 2010; 3. Mathew P. Semin Hematol. 2006;43(suppl 4):S8-S13. 71

82 Thank You 72