Treatment of von Willebrand disease. Jenny Goudemand Haematology Department University Hospital of Lille - France

Transcription

1 Treatment of von Willebrand disease Jenny Goudemand Haematology Department University Hospital of Lille - France

2 French registries on VWD Inclusion criteria FranceCoag Network French Institute for Public Health Surveillance Type 3 VWD Type 2 VWD VWF:Rco or VWF:CB/ VWF:Ag ratio <0.7 FVIII/VWF:Ag ratio <0.5 RIPA positive at low (>0.8 mg/ml) ristocetin concentration Type 1 VWF:Ag <30% CRMW National Reference Center on VWD University Hospital of Clamart-Lille Clinical events Treatment Comorbidities 690 pts included in both Type 3: 33 (7%) Type 1: 56 (12%) Type 2: 366 (82%) Not yet classified:235 (35%) Phenotype Genotype Classification Bleeding score 1319 pts 1601 pts February 2012

3 FranceCoag network: 1319 pts Age 0-11yrs: 203 (15%) yrs: 400 (30%) 12-31yrs: 408 (31%) yrs: 308 (23%) Sex ratio (M/F): 0.80 Median follow up (years): 1.8 (IQ: ) Events during follow up: q 106 severe bleedings in 48 pts q 859 surgeries or invasive procedures in 444 pts q 18 deaths

4 Severe bleedings (n=106) Episodes (n=106) Pa2ents (n=48) GI bleedings Mucocutaneous bleedings 8 8 Intra cranial bleedings 7 6 Intra or retroperitoneal bleedings 3 3 Haematoma 3 3 Pregnancy or post delivery bleedings 3 3 Other 7 6 Severe bleedings are defined as life threatening bleedings

5 Surgeries or invasive procedures (n=859) Type of surgery Number (%) Diges2ve and urologic 184 (21.4%) Dental extrac2ons 160 (18.6%) Trauma and orthopedic 142 (16.5%) ENT 86 (10.0%) Delivery 86 (10%) Gynecologic 60 (7.0%) Cardio vascular 41 (4.8%) Ophtalmic 24 (2.8%) Pulmonary 9 (1%) Neuro surgery 3 (0.3%) Other 64 (7.5%)

6 Treatments during the follow up periode 745 patients (56.5%) were not treated 568 (43%) received an haemostatic treatment ddavp only: 119 (21%) Replacement therapy only 397 (70%) q VWF concentrates only: 184 (46 %) q VWF + FVIII concentrates: 211 (53 %) q FVIII concentrates only: 2 (<0.01 %) ddvap or replacement therapy 52 (9%) q ddavp or VWF concentrates: 27 (52 %) q ddavp or VWF + FVIII concentrates: 25 (48 %) Unknown: 6 pts (0.5 %)

7 Treatment of patients with VWD: what are the tools?

8 Adjunctive therapies Anti fibrinolytics q Tranexamic acid (or aminocaproic acid) q Effective in the treatment of epistaxis, oral bleedings, menorrhagia tissues with a high fibrinolytic activity Topical agents q Topical collagen sponges q Calcium alginate q Oxidized cellulose Estrogens progestogens q Essential in the management of menorrhagia q Should be started early in adolescents

9 Desmopressin Desmopressin (ddavp) : a synthetic derivative of vasopressin Stimulates the release of VWF and tpa from Weibel Palade bodies and causes a simultaneous increases in FVIII Desmopressin can be infused IV (0.3 µgkg -1 ) or given intranasally ( µg) Effects: q VWF: 2-3-fold increase q FVIII: 2-5-fold increase q Peak: observed min after infusion q Half life: 6-9 hr for VWF, 5-6 hr for FVIII The effect is reproducible for a same individual Children less than 2 yrs old have significantly lower response than adults Averse effects: water retention if strict fluid restriction is not observed; not to be used in elderly patients with atherosclerosis or with hypertension Due to large intra individual variability: a test dose is recommended soon after diagnosis

10 Infused in 30 ml saline over 30 Castaman Revel-Vilk Federici CRMW ddavp hr Castaman et al. (2008) Revel- Vilk et al. (2003) Evalua2on 2me 1 hr a6er the beginning of infusion (peak) 1hr a6er the end of infusion (peak) Response Complete response Par?al response No response VWF:RCo and FVIII levels 50% <50% <50% Increase over baseline values 3- fold <3- fold Good response 30% 2- fold Federici et al. (2004) 2 hrs a6er the end of infusion Good response 30% and BT <12 min 3- fold CRMW 2 hrs a6er the end of infusion Complete response Par?al response No response 50% <50% <50% 3- fold <3- fold

11 Response to desmopressin Complete response Partial response No response Castaman et al. (2008) Type (83%) 10 (13%) 3 (4%) Revel-Vilk et al. (2003) Type 1 Type 2A (80%) 1 (40%) 14 (20%) Federici et al. (2004) Type 1 Type 2A Type 2M (27%) 1 (7%) 3 (14%) 19 (73%) 14 (93%) 18 86%) Type 2N 4 3 (75%) 1 (25%) Type 2B: Should not be used (except may be in case of some muta?ons: P1266L, P1266Q, R1308L without thrombocytopenia, Federici 2009) Type 2N: good response in pa?ents with the R854Q muta?on but incomplete response in those with the R816W or C1060R muta?on (Mazurier, 1994; Federici 2004)

12 PFA-100 monitoring of VWF response to desmopressin 2A 2B 2B NY 2M 2M B Type 1 Type 2 Fressinaud et al. BJH 1999

13 ddavp reponse in Type 1 Vicenza (R1205H) Several other mutations can affect the VWF clearance and explain a short post ddavp survival of VWF in type 1 Millar et al. TH : Ú So it is probably more clinically relevant to evaluate the response at later times (2 hr) Casonato A et al. Blood 2002;99:

14 Clinical use of desmopressin Tachyphylaxis: 2 de infusion is 30% less effective than the 1 rst ; so it is advisable not to administer more than 2-4 infusions Short term administration q Invasive procedures q Dental extractions q Some minor surgeries q Menorrhagia: effective in most of the cases but home treatment has also to be strictly monitored to avoid water retention q Pregnancy? Some experiences presented but usually not registered in this situation

15 VWF concentrates Most of them are FVIII/VWF concentrates q Differing by SA, FVIII/VWF ratio, the preservation of HMWM, the VWF:RCo or CB/VWF:Ag ratio, the viral inactivation procedures, sources of plasma Currently there is only 1 concentrate that contain only VWF with almost no FVIII q pd VWF concentrate q rvwf concentrate will be subsequently available expressed in CHO cells differs from the pdvwf by the presence of UL MWM cleaved in smaller multimers upon exposure to ADAMTS13 main biological activities (VWF:RCo, VWF:CB, FVIII binding capacity) are comparable to pdvwf

16 Product (manufacturer) Process Viral inactivation SA: RCo/ mg SA: FVIII/ mg Alphanate/Fanhdi (Grifols) Heparin ligand chromatography 1: SD 2: Dry heat (80 C, 72h) Biostate (CSLBehring) Heparin glycin precipitation 1: SD 2: Dry heat (80 C, 72h) 50 Factor 8Y (BPL) Heparin/glycine precipitation 1: Dry heat (80 C, 72h) Haemate P/Humate P (CSLBehring) Multiple (glycine/nacl) precipitation 1: Wet heat (60 C, 10h) <50 Immunate (Baxter) Ion exchange 1: SD 2: Wet heat (60 C, 10h) 70 ±30 Koate DVI (Talecris) Multiple precipitation, size exclusion chromatography 1: SD 2: Dry heat (80 C, 72h) <50 Wilate (Octapharma) Ion exchange, size exclusion 1: SD 2: Dry heat (80 C, 72h) 101 ± ± 26 Wilfactin/Willfact (LFB) Ion exchange, affinity chromatography 1: SD 2: 35 nm filtration 95 ± 15 NA 3: Dry heat (80 C, 72h)

17 Product (manufacturer) Alphanate/Fanhdi (Grifols) Biostate (CSLBehring) Factor 8Y (BPL) Haemate P/Humate P (CSLBehring) Immunate (Baxter) Koate DVI (Talecris) Wilate (Octapharma) Wilfac2n/Willfact (LFB) VWF:RCo (U) per 1 U VWF:Ag VWF:CB (U) per 1 U VWF:Ag FVIII:C (U) per 1 U VWF:Ag NA NA <0.1

18 PK characteristics of Wilfactin in type 3 VWD patients Plasma levels (IU/dL) VWF:Rco VWF:Ag FVIII:C 6 patients: Dosage : RCo: 60 IU/kg FVIII: 1.5 IU/kg Hours post-injection FVIII synthesis rate : 6 IU/dl/h FVIII half life (h): 15 hrs Goudemand J et al, JTH, 2005

19 Product (manufacturer) VWD types no pts VWF:RCo Recovery (%/U/kg) T 1/2 (h) Recovery (%/U/kg) FVIII T ½ (h) Authors Alphanate/ Fanhdi (Grifols) Biostate (CSL Behring) Type Mannucci, 2002 various 12 85% % 28.6 Favaloro, 2007 Factor 8Y (BPL) Type 3 various Lubetsky, 2002 Haemate P/ Humate P (CSLBehring) Type 3 various Kessler, 2011 various Di Paola, 2011 Immunate (Baxter) various various % % Ver Elst, 2004 Auerswald, 2002 Wilate (Octapharma) Type 3 various Kessler, 2011 Wilfactin/ Willfact Type 3 various NA NA Goudemand, 2005 (LFB)

20 Surgery: target levels and dosing recommandations (Pasi 2004, Nichols 2008, Mannucci 2009) Major Minor Rco U/kg Target levels Duration US Pre loading FVIII RCo >100% Post ev 8-24h FVIII RCo >50% 7-10 days UK Pre FVIII 100% Post FVIII RCo >50% 7-10 days Italy Pre 50 loading FVIII >50% 5-10 days Post 50 ev 24 h US Pre loading FVIII RCo >30% Post ev h FVIII RCo >30% 1-5 days UK Pre Post Italy Pre loading Post Ev o d FVIII >30% 2-4 days

21 Special recommendations when using VWF concentrate with a low FVIII content to cover the per-operative period 3 options VWF alone (if the baseline FVIII is 20 IU/dL) 1 2 co administer FVIII (20-30 IU/kg) at the 1rst infusion of VWF (50-60 IU/kg); specially in case of unscheduled surgery give 2 pre operative infusions of VWF (50-60 IU/kg) at 12-18h interval; in case of scheduled surgery 3 Post operative period: VWF is administered without any additional FVIII 44% 44% Pivotal study n: % 37% PMS study n: % 44% Borel-Derlon

22 Efficacy in surgery Authors Product no surg. Mannucci 2002 Federici 2010 Hernandez 2008 Dunkley 2010 Gill 2011 Ver Elst 2004 Viswabandy a2008 Windyga, 2011 Borel-Derlon 2007 VWF:RCo U/kg/d FVIII U/kg/d no infusions Alphanate to 40 3 (1-18) Fanhdi to (1-37) Fanhdi Mean:20 (12-35) Biostate to (3-35) Haemate to (2-55) no exposure days 3-7 (1-24) 1-5 (1-26) Immunate (1-6) Koate DVI to 20 7 (3-11) Wilate to (1-29) Wilfactin (1-65) 3 (1-57) Overall efficacy 96% 99% 98% 87% 91% 80% 90% 96% 100%

23 Thrombotic risk in surgery q Repeated infusions can lead to accumulation of FVIII q FVIII:C 150 IU/dL: an independent risk factors of venous thrombosis (Koster, 1995) q Thrombotic risk is reinforced in surgery due to: Inflammatory process (increased Fg, platelets ) Type of surgery Patient s conditions q FVIII:C should not exceed 250 IU/dL (Nichols et al. 2008) è more easy to respect with a VWF concentrate without FVIII

24 Spontaneous bleedings To be controlled: Mucosal bleedings require the correction of VWF platelet dependent functions highly dependent on the presence of HMWM Non mucosal bleedings mainly require the correction of the FVIII deficiency Dosage recommendations are not very different from those used in surgery

25 Efficacy in bleeding episodes Authors Product no episodes VWF:RCo (U/kg/d) FVIII:C (U/kg/d) no infusions no exposure days Overall efficacy Mannucci 2002 Federici 2010 Dunkley 2010 Lillicrap 2002 Federici 2007 Alphanate % Fanhdi (1-40) 97% Biostate (1-10) 4/6 Haemate P % Haemate P % Berntorp Wilate (1-29) 96% Borel- Derlon 2007 Wilfactin FVIII 38% 3 (1-46) 3 (1-37) 89% PMS Wilfactin FVIII 34% 9 (1-50) 6 (1-47) 94%

26 Gastro intestinal bleedings In up to 10% of cases, VWD is associated with angiodysplasia (Fressinaud, 1993) In the Win study GI bleedings are the 2d cause for initiating treatment (transfusion, desmopressin, replacement therapy) after CNS bleeding (de Wee et al. TH 2012) These GI bleedings are specially difficult to control q Pointed out in several studies (Berntorp, 2009; Borel-Derlon 2007, q Dunkley, 2010; Federici 2010; Abshire 2012) Long term prophylaxis has been proposed but there are some failures (Basso 2004; Makris 2006; Sohal 2008) The lack of VWF promotes angiogenic processes (Starke, 2011) Replacement therapy alone could be probably not sufficient in some patients Combined therapy with antiangiogenic drugs could be explored (although limited by side-effects)

27 Long term prophylaxis Long term prophylaxis* is considered in case of recurrent mucosal and/or joint bleeding q q To reduce the bleeding and their consequences (chronic anaemia, transfusion requirement, impaired quality of life) To prevent the arthropathy Recent retrospective analysis (Abshire et al. 2012): q 60 patients (57% type 3) q treated for epistaxis (24%), GI bleedings (24%), joint bleedings (22%), menorrhagia (7%), other (23%) q 2-3 infusions/week at a median dose U/kg for a median period of 2.2 years q Significant reduction in annualized bleeding rate Prospective studies are on going (VIP study, Pro Will study) * >1 injection per week for 45 weeks annually (Lethagen, 2006)

28 Conclusions The treatment of patients with VWD is probably more complex than hemophilia due to the variety of clinical situations encountered and to the heterogeneity of patients with VWD. The therapeutic approach may vary from complete therapeutic abstention, use of adjunctive therapies, proper use of desmopressin, to the institution of a more or less prolonged replacement therapy. Contrary to hemophilia, only a few patients may probably justify prophylaxis but the therapeutic regimens should be better defined. Current treatments for VWD are both effective and safe in most instances.