Inhibitors in Congenital Hemophilia

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  • Time to success by treatment arm. (A) Kaplan-Meier plot showing thetime to tolerance for the 66 patients who achieved a success, partial success, orfailure end point, broken down by HD and LD treatment arm. (B) Intention-to treatKaplan-Meier plot showing the time to tolerance for all 115 patients randomized andbroken down by treatment arm. This plot shows no significant difference betweentreatment arms (P .942), but a lower success rate because those not completingITI or who were withdrawn for logistical reasons are also included.
  • Inhibitors in Congenital Hemophilia

    1. 1. LISA N BOGGIO, MS, MD RUSH UNIVERSITY MEDICAL CENTER Inhibitors in Congenital Hemophilia
    2. 2. Faculty Disclosure  CSL Behring – Advisory Board, Investigator  Novo Nordisk – Investigator  Baxter – Advisory Board, Investigator  Bayer – Investigator  Biogen-Idec - Investigator
    3. 3. Educational Objectives  Identify patients at risk for developing factor VIII (FVIII) and factor IX (FIX) inhibitors  Evaluate treatment options for the management of acute bleeding episodes in patients with inhibitors  Discuss therapeutic options for the prevention of bleeding in the surgical and nonsurgical setting
    4. 4. Introduction  Congenital bleeding disorder  X-linked  Deficiency of FVIII or factor IX  80%-85% FVIII deficiency (hemophilia A)  60% is severe hemophilia  15% moderate  25% mild
    5. 5. Recurrent Joint Bleeding ©2009 Rush University Medical Center. Right Left
    6. 6. Inhibitors  Occur in up to 30% of patients with severe (<1% FVIII) hemophilia A  0.9%-7% of those with mild to moderate hemophilia A  3% of those with hemophilia B  Do not increase mortality, but bleeding more difficult to control  Uncontrollable hemorrhage, devastating joint disease and disability
    7. 7. What Is an Inhibitor?  Antibody to FVIII molecule  IgG4 subclass  Does not fix complement  No immune complex disease  Measured in Bethesda units (BU)  Normal, <0.6 BU  Low-responding inhibitor, 0.6-5 BU  Transient or persistent  High-responding inhibitor, >5 BU  Anamnestic response
    8. 8. Mechanisms of FVIII Inhibitor Action Scandella D. Vox Sang. 1999;77 (suppl 1):17-20. FX interaction A2A3 FIXa Interactions C1 C2 Phospholipid interaction FVIIIa A1
    9. 9. Bethesda Unit Kasper CK et al. Thromb Diath Haemorrh. 1975;34:869-872. BU per mL Plasma 1 BU = amount of inhibitor that inactivates half of FVIII in incubation mixture ResidualFVIII(%ofcontrol) 100 75 50 25 10 0 0.4 1 2
    10. 10. Genetics of FVIII Inhibitors Schwaab R et al. Thromb Haemost. 1995;74:1402-1406.  Certain molecular abnormalities are highly associated with inhibitor development  Large deletions (69% risk)  Stop mutation (35% risk)  Inversion of intron 22 (39% risk)  Absence of protein may be associated with inhibitor development
    11. 11. Inhibitor Prevalence in Hemophilia A Oldenburg J, Pavlova A. Haemophilia.2006;12 (suppl 6):15-22. Multidomain 88% Large deletions 41% Intron 22/1 inversions 21%/17% Single domain 25% Light chain 40% Nonsense 31% Heavy chain 40% Non–A-Run 21% Small deletions 16% Splice site 17% A-Run 3% C1-C2 Missense Non–C1-C2 10% 5% 3% 100 75 50 25 0 InhibitorPrevalence(%)
    12. 12. Incidence of Inhibitors Lusher JM et al. N Engl J Med. 1993;328:453-459. Bray G. Ann Hematol. 1994;68(suppl 3):S29-S34.  FVIII: 15%-30%  Less pure products may produce lower titer inhibitor  Intermediate purity, 20%  Monoclonal products, 16%  Recombinant products, 24%  25%: transient inhibitor  30%: low-responding inhibitor  45%: high-responding inhibitor
    13. 13. Onset of Bleeding and Inhibitors in Patients With Severe Hemophilia Pollmann H et al. Eur J Pediatr. 1999;158(suppl 3):S166-S170. <5 BU >5 BU 100 80 60 40 20 0 Patients(%) FVIII Exposure (days) 0 50 100 150 200 250 %WithBleeding 100 80 60 40 20 0 Age (years) 0 1 2 3 4 5 Bleeding All patientsJoint Other White GC II et al. Am J Hematol. 1982;13:335-342.
    14. 14. Inhibitor Development Lusher JM et al. N Engl J Med. 1993;328:453-459; Bray G. Ann Hematol. 1994;(suppl 3):S29-S34; McMillan CW et al. Blood. 1988;71:344-348.  Inhibitors usually develop in young patients  Median, 20 months for pure products  Present later in life for less pure product  2% incidence for previously treated adults  Inhibitor development occurs in severe hemophilia (<2% FVIII activity)  Mild-moderate (2.5% incidence)  Inhibitors develop early after exposure: median, 9 doses
    15. 15. Treatment-Related Risk Factors for Inhibitor Gouw SC et al. Blood. 2007;109:4648-4654.  CANAL: Retrospective cohort study in 366 patients with severe hemophilia A  Age at first exposure  Incidence ↓ from 41% in patients treated within first month of age to 18% in patients first treated after 18 months  Association largely disappeared after adjustment for treatment intensity  ↑ risk associated with surgical procedures and peak treatments  60% lower risk in patients on prophylactic vs on-demand treatment
    16. 16. Risk Factors for Inhibitor Development Viel KR et al. N Engl J Med. 2009;360:1618-1627; Ragni MV et al. Haemophilia. 2009;15:1074-1082. • Mismatched recombinant FVIII replacement therapy may be a risk factor for inhibitor development in black patients • In a prevalent case-control study of 950 patients with hemophilia A enrolled in the Hemophilia Inhibitor Study (HIS), the following are risk factors for inhibitor development – High intensity product exposure – CNS bleeding – African-American race – Lack of missense mutations
    17. 17. Treatment Modalities  Control Bleeding  High dose factor replacement  Porcine factor VIII  Bypassing agents  Prothrombin complex concentrates  Recombinant factor VIIa  Eradicate inhibitor  Immune tolerance induction
    18. 18. Control Bleeding  High dose factor  Only helpful for low titer inhibitors  Bypassing products  Porcine factor VIII  Activated prothrombin complex concentrate (aPCC)  Recombinant factor VIIa (rFVIIa)
    19. 19. Porcine Factor VIII Morrison et al. Blood 1993: 1513  Not currently available  Can follow factor VIII activity  Complications: inhibitor, thrombocytopenia, DIC  Study of 64 patients with acquired inhibitor  Bleeding control  Excellent 26  Good 24  Fair or poor 14  Average dose 90 U/kg q12 hours
    20. 20. Activated Prothrombin Concentrates Sjamsoedin LJ et al. N Engl J Med. 1981;305:717-721; Hilgartner MW et al. Blood. 1983;61:36-40. • More effective than prothrombin concentrates (PCC) • Dose: 50-75 U/kg, every 12 hours as needed for bleeding resolution • 36% of patients respond to a single dose of aPCC 50 U/kg within 12 hours • Doses >200 U/kg/d associated with increased risk for thrombosis • Complications more prevalent than with PCC – Especially disseminated intravascular coagulation – Rare complications: MI, PE, DVT, allergic reactions
    21. 21. Recombinant Factor VIIa Young G et al. Haemophilia. 2008;14:287-294; Kavakli K et al. Thromb Haemost. 2006;95:600-605.  Mechanism of action: activation of FIX and FX  Thrombin generation (amount and rate) essential  Conventional dosing: 90 µg/kg every two hours until hemostasis achieved  Recent studies demonstrated that 270 μg/kg single dose similar to 90 μg/kg x 3  Gradually increase dosing interval as patient improves
    22. 22. Recombinant FVIIa Dosing Key NS et al. Thromb Haemost. 1998;80:912-918; Lusher JM. Blood Coag Fibrinolysis. 2000;11 (suppl 1):S45-S49.  Package insert: dose, 90-120 µg/kg  Clinical studies indicate that an average of 2.2 doses are needed to control a bleed at these doses  Earlier treatment results in better outcome  23% of patients respond to a single dose of rFVIIa 90 µg/kg within 3 hours
    23. 23. aPCC vs rFVIIa Astermark J et al. Blood. 2007;109:546-551; Young G et al. Haemophilia. 2008;14:287-294.  Each alone is effective in about 70%-90% of bleeds  Two prospective studies compared aPCC and rFVIIa head to head  FENOC study (investigator-initiated sponsored by Baxter)1  F7Haem-2068 (industry-initiated sponsored by Novo Nordisk)2
    24. 24. FENOC Study FENOC = FEIBA NovoSevenComparative .Astermark J et al. Blood. 2007;109:546-551. • Randomized, open-label study comparing single dose of aPCC 75-100 U/kg vs 2 doses of rFVIIa 90- 120 µg/kg • Primary end points – Hemostatic efficacy – Pain • Results – aPCC and rFVIIa appear to exhibit a similar effect on joint bleeds – Statistical criterion of equivalence not met
    25. 25. FENOC Study: Efficacy Outcomes  No statistically significant differences in the distribution of outcomes by treatment at any time point  Primary endpoint of equivalence not met Astermark J et al. Blood. 2007;109:546-551. Frequency 50 40 30 20 10 0 4836 Effective Poorly effective Not effective Partially effective aPCC Hour Treatment 2 6 12 24 2 6 12 24 36 48 rFVIIa
    26. 26. F7Haem-2068: Study Design The rFVIIa doses were blinded and placebo-controlled. First bleed T0 T+3h T+6h 27 patients with hemophilia + inhibitors rFVIIa 270 μg/kg Placebo Placebo rFVIIa 90 μg/kg rFVIIa 90 μg/kg rFVIIa 90 μg/kg aPCC 75 U/kg rFVIIa 270 μg/kg Placebo Placebo rFVIIa 90 μg/kg rFVIIa 90 μg/kg rFVIIa 90 μg/kg aPCC 75 U/kg rFVIIa 270 μg/kg Placebo Placebo rFVIIa 90 μg/kg rFVIIa 90 μg/kg rFVIIa 90 μg/kg aPCC 75 U/kg Second bleed T0 T+3h T+6h Third bleed T0 T+3h T+6h Young G et al. Haemophilia. 2008;14:287-294.
    27. 27. F7Haem-2068: Hemostasis Achieved Key et al, 92%; Kavakli et al, 90.5%; Young G et al. Haemophilia. 2008;14:287-294. 91.7 90.9 0 20 40 60 80 100 PatientsNotNeedingRescue Medicationat9h(%) 22/24 rFVIIa 270 μg/kg single dose rFVIIa 3 x 90 μg/kg multiple doses 20/22 aPCC 75 U/kg 63.6 14/22 *P = 0.032 P = 0.069
    28. 28. F7Haem-2068: Summary Young G et al. Haemophilia. 2008;14:287-294.  A significant reduction in the use of rescue medications occurred in the single-dose rFVIIa 270- μg/kg group compared with aPCC  A trend to significance was also noted in the multiple-dose rFVIIa arm vs aPCC  This may be biased by the study design
    29. 29. Prophylaxis for Patients With Inhibitors  Potential benefits  Reduce incidence of bleeding  Allow for more normal quality of life  Resolve target joint  Prevent joint damage  Improve overall functioning prior to major surgery
    30. 30. rFVIIa Prophylaxis Study: Konkle BA et al. J Thromb Haemost. 2007;5:1904-1913. Preprophylaxis Period Postprophylaxis Period Prophylaxis Period MeanNo.ofBleedsperMonth 7 6 5 4 3 2 1 0 90 µg/kg 270 µg/kg * +35%; +22% *** *** – 45%; –59% ** *** – 27%; –50% Bracketed data are the estimated changes (%) in no. of bleeds/month (defined as 28 days) for the 90 µg/kg and 270 µg/kg rFVIIa treatment groups during the prophylaxis or postprophylaxis period as compared with the preprophylaxis period, and during the prophylaxis period as compared with the postprophylaxis period. ***P≤0.001; **P≤0.01; *P≤0.05.
    31. 31. rFVIIa Prophylaxis Quality of Life Hoots WK et al. Haemophilia. 2008;14:466-475 80 60 40 20 0 %PatientsWithNoProblems Mobility Screening Preprophylaxis End of Prophylaxis End of Postprophylaxis EQ-5D dimension Anxiety Self-care Pain Unusual activities
    32. 32. aPCC Prophylaxis Case Series Joint ROM Bleeding Author Year N Unit/Wk Better No Δ Worse Reduction Valentino 2009 6 700 NR NR NR 100% Leissinger 2007 5 225 1 4 0 78% Ohga 2007 1 150 NR NR NR 100% DiMichele 2006 1 4 245 3 8 2 53% Siegmund 2005 1 210 1 0 0 NR Hilgartner 2003 7 375 2 NR 7 NR
    33. 33. aPCC Prophylaxis: Efficacy DiMichele D, Négrier C. Haemophilia. 2006;12:352-362. Excellent/GoodEfficacy(%) Pre-/Intraoperative Postoperative 0 10 20 30 40 50 60 70 80 90 100
    34. 34. Eradicate Inhibitor CTX = cyclophosphamide; IVIg = intravenous immunoglobulin; EACA = epsilon aminocaproic acid. Regimen FVIII Other Bonn 100-150 IU/kg bid aPCC prn Los Angeles 50 IU/kg/d Steroids Malmö Keep FVIII >0.40 CTX, IVIg, EACA van Creveld 25 IU/kg alternate days Oxford On demand Immune Tolerance Induction (ITI)
    35. 35. Defining Outcome With ITI International consensus • Undetectable inhibitor titer <0.6 BU – By Bethesda or Nijmegen assay and • Normalized FVIII pharmacokinetics – Plasma FVIII recovery >66% of expected and – Half-life >6 h after 72-hour FVIII exposure-free period
    36. 36. Evidence-Based Approach to ITI ITI failure • Failure to attain the definition of success within 33 months of uninterrupted ITI • Failure to demonstrate a progressive 20% reduction in inhibitor titer over each successive 6-month period of uninterrupted ITI, beginning 3 months after initiation to allow for expected anamnesis
    37. 37. Factor IX Inhibitors in Hemophilia B DiMichele D. Br J Haematol. 2007;138:305-315. 42  Occur in 3% of patients  Approximately 80% are high-responding  Frequent occurrence of allergic/anaphylactic reactions prior to or simultaneously with the onset of inhibitors  Antibodies to FIX protein  IgG4 and IgG1 subclasses
    38. 38. Hemophilia B: Genetics Belvini D et al. Haematologica. 2005;90:635-642. 43 • Type of mutations: missense (69.5%), nonsense (14.4%), small deletions (6.4%), splice site (5.9%), large deletions (2.5%), promoter mutations (1.3%) • Correlation with disease severity – Deletions, nonsense mutations: severe hemophilia B (HB) – Missense mutations: mild HB (88%), moderate HB (90%), severe HB (59%) • Mutation type and risk for inhibitor development – Inhibitors in 4.7% with severe HB – Large deletions, nonsense mutations, frameshift
    39. 39. ISTH-SSC International FIX Inhibitor Registry 44  Focus on patients with FIX inhibitor-related complications (severe allergic or anaphylactic reactions)  Median age at inhibitor detection: 19.5 months (9- 156)  Median exposure days to FIX replacement therapy: 11 days (2-180)  Mean peak inhibitor titer: 30 BU (1-1156)
    40. 40. Success Rate of ITI Regimens for FVIII Inhibitors International and North American ITI Studies; reported at Bonn, August 1997. International North American Combined Success 114 (69%) 93 (72%) 207 (70%) Failure 51 (31%) 37 (28%) 88 (30%)
    41. 41. Prognostic Factors for ITI Host Factors IL = interleukin; TNF = tumor necrosis factor-alpha. DiMichele D. J Thromb Haemost. 2007;5(suppl1):143-150. • No single host-related variable has been shown to be specific and sufficient for predicting anti-FVIII antibody development – Hemophilia severity – FVIII gene mutation (null mutations) – Ethnicity – Family history – IL-10 (odds ratio, 4.4) and TNF polymorphism
    42. 42. F8 Gene Mutations and ITI Outcome Rocino A et al. Haematologica. 2006;91:558-561.  Successful ITI  12/17 (70%) of patients with intron 22 inversion  5/7 (75%) of patients with other null mutations  Null mutations did not affect chance of achieving successful ITI
    43. 43. Coppola A et al. J Thromb Haemost. 2009;7:1809-1815.
    44. 44. ITI Success and F8 Mutation Coppola A et al. J Thromb Haemost. 2009;7:1809-1815. Low risk High risk 20 40 60 80 100 CumulativeITISuccessRate(%) 0 0 5 10 15 20 Time (months) 403025 35
    45. 45. Prognostic Factors for ITI DiMichele D. J Thromb Haemost. 2007;5(suppl 1):143-150.  Pre-ITI titer  Historical peak titer  Dose of FVIII concentrate  FVIII product type  Immune modulation  Supportive care  Bypass therapy bleeding prophylaxis
    46. 46. Influence of Inhibitor Titer DiMichele D. J Thromb Haemost. 2007;5(suppl 1):143-150.
    47. 47. International ITI Study: Results Hay and DiMichele. Blood. 2012; 119: 1335
    48. 48. Time to Tolerance Hay and DiMichele. Blood. 2012; 119: 1533 Intent to Treat Group Responding Group
    49. 49. ITI Milestones By Treatment Arm Hay and DiMichele. Blood. 2012; 119: 1533 n LD n HD p Phase 1: start of ITI to negative titer 29 9.2 (4.9-17.0) 31 4.6 (2.8-13.8) .017 Phase 2: negative titer to first normal recovery 27 13.6 (8.7-19.0) 23 6.9 (3.5-12.0) .001 Phase 3: normal recovery to tolerance 24 15.5 (10.8-22.0) 22 10.6 (6.3-20.5) .096
    50. 50. Work Still Needs To Be Done  Role of gene haplotypes in inhibitor development  Rates of inhibitor development in PUPs with plasma- derived factor (SIPPET)  Inhibitor rates with long-acting factors

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