Bevacizumab (Avastin) Neus Spray voor Frequente Neusbloedingen bij ROW

Proefbehandeling

F.S. van der Meer, MDSt Antonius hospital Nieuwegein,, The Netherlands

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ROW en neusbloedingen (epistaxis)

- > 90% terugkerende epistaxis- Frequent ijzer and bloedtransfusies- Verstoort dagelijkse leven en werk

- Meeste behandelingen hebben tijdelijk effect of veel bijwerkingen- Laser, embolisation, surgery: Saunders- Estrogen (de pil),- Thalidomide

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Bevacizumab (Avastin)

Eerder onderzoek:- Patienten met ROW hebben verhoogde spiegels van VEGF

(oa Saddic et al, 2005)

-Menselijk antilichaam-Bind aan en remt VEGF activiteit

-Iremt vaatgroei

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Eerdere Bevacizumab publicaties, lokale toepassingDavidson TM, Olitsky SE, Wei JL. Hereditary hemorrhagic telangiectasia/avastin

Laryngoscope 2010:

- Case report, male 45 yrs, HHT, recurrent epistaxis

- Injection submucosal 100mg Bevacizumab• <1 wk epistaxis stopped• effect: 3-4 months

- Nasal spray 10mg/ml, 2wk, total 50mg• <1 wk epistaxis stopped• effect 3-4 months

- Nasal spray 25mg/ml, every 30min 1 spray till 25mg• effect 2.5 months

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Eerdere Bevacizumab publicaties, lokale toepassingKarnezis TT, Davidson TM. Efficacy of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis

Laryngoscope 2011:

- 32 patients: • 17 topical, spray, 50-100mg, • 10 submucosal injection, 100mg (125mg), • 5 topical spray and submucosal injection, • 12/32 also KTP laser

•Follow-up:- ESS before treatment and 2-18 (mean 4.1) months after treatment

•Results: - ESS pre treatment 7.0, after treatment: 2.9 - ( 17 topical: 6.6- 3.6, 10 submucosal 8.1- 2.1)

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Eerdere Bevacizumab publicaties,lokale toepassing

VeiligheidChen S 4th, Karnezis T, Davidson TM. Safety of intranasal Bevacizumab (avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis.

Laryngoscope 2010:

52 patients, treated with bevacizumab intranasally applied, some on mutiple occasions- Topical spray, 50-100mg Bevacizumab (26) KTP 0- Submucosal injection, 25-100mg bevacizumab, (34), also KTP (30)

•Follow-up 1.5-46 months after treatment:- 5 septal perforation (all combined submucosal injection and KTP laser)- No other common or serious event

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Proefbehandeling

Bevacizumab nasal spray- Solution 25mg/ml, dose 0.1ml (2.5mg)- Daily use: 2dd1 both sides (0.4ml=10mg)- Treatment duration: 1 week (70mg)

-Inclusion of 8 HHT patients with recurrent epistaxis-All signed informed consent

-Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment- Validated in previous studies-Hb, ferritin levels before and after treatment-Video of nasal mucosa before and after treatment

-June and August 2011:-2 and 4 months after treatment evaluation-4 weeks diary, hb/iron/ferritine levels

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Pilot treatment

Bevacizumab nasal spray- Solution 25mg/ml, dose 0.1ml (2.5mg)- Daily use: 2dd1 both sides (0.4ml=10mg)- Treatment duration: 1 week (70mg)

-Inclusion of 8 HHT patients with recurrent epistaxis-All signed informed consent

-Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment- Validated in previous studies-Hb, ferritin levels before and after treatment-Video of nasal mucosa before and after treatment

-June and August 2011:-2 and 4 months after treatment evaluation-4 weeks diary, hb/iron/ferritine levels

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Pilot treatment

Bevacizumab nasal spray- Solution 25mg/ml, dose 0.1ml (2.5mg)- Daily use: 2dd1 both sides (0.4ml=10mg)- Treatment duration: 1 week (70mg)

-Inclusion of 8 HHT patients with recurrent epistaxis-All signed informed consent

-Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment- Validated in previous studies-Hb, ferritin levels before and after treatment-Video of nasal mucosa before and after treatment

-June and August 2011:-2 and 4 months after treatment evaluation-4 weeks diary, hb/iron/ferritine levels

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Pilot treatment

Bevacizumab nasal spray- Solution 25mg/ml, dose 0.1ml (2.5mg)- Daily use: 2dd1 both sides (0.4ml=10mg)- Treatment duration: 1 week (70mg)

-Inclusion of 8 HHT patients with recurrent epistaxis-All signed informed consent

-Diary of epistaxis during 4 weeks before treatment and 4 weeks after treatment- Validated in previous studies-Hb, ferritin levels before and after treatment-Video of nasal mucosa before and after treatment

-June and August 2011:-2 and 4 months after treatment evaluation-4 weeks diary, hb/iron/ferritine levels

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InclusionPatients (8) Age (yrs) Sex (m/f) Type HHT Previous

treatmentsIron/bloodtransfusions

1 68 m HHT-1 LaserArgonlaser

Iron and blood iv every 3wks

2 68 f HHT-1 LaserArgonlaserSeptumbutton

Oral iron

3 68 m HHT-1 ArgonlaserSaundersThalidomide stopped 2009Sitaglyptine

Oral iron

4 60 f HHT-2 ArgonlaserSaundersEstrogen

Oral iron

5 68 f HHT-2 LaserEmbolisationThalidomide stopped 2-25-2011

Iron iv every week

6 51 f HHT-1 EmbolisationWeekly visit ENT

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7 72 m HHT-2 SaundersArgonlaser

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8 60 m HHT-2 LaserArgonlaserseptumbutton

-

Mean 64.4 50% male 50% HHT-1

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ResultsFreq epistaxis/day Duration of

epistaxis min/daySeverity of epistaxis1-2-3

Patients opinion of bleeding

before

after diff before

after diff Before

after diff During treatment After treatment

1 2.9 2.6 -0.3 9.6 13 +3.4 1.3 1.6 +0.3 = Shorter

2 1.5 0.6 -0.9 77.0 33.9 -43.1 2.7 2.7 0 Heavy bleeding Less freq

3 3.0 2.1 -0.9 30.1 15.1 -15 2.6 2.4 -0.2 More bleeding Less freq less severe

4 1.3 1.0 -0.3 15.6 8.8 -6.8 1.0 1.1 +0.1 More bleeding =

5 0.9 0.9 0 12.6 80 +67.4 1.5 1.5 0 Severe bleeding Less severe, wholeday bleeding

6 3.7 0.9 -2.8 6.1 3.0 -3.1 1.1 1.1 0 More bleeding Less

7 0.5 0.2 -0.3 7.4 2.5 -4.9 1.6 1.5 -0.1 Some bleeding Less

8 1.6 1.1 -0.5 42.0 14.6 -27.4 1.3 1.2 -0.1 More bleeding Less

Median 1.55 0.95 14.1 13.0 1.64 1.63

-56%

-50%

-52%

-66%

-65%

+500%

p 0.757 / 0.065 p 0.049

Paired samples T-test

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ResultsHb level Ferritin Patients opinion of bleeding

patients before after Before after During treatment After

1 7.2 6.8 23 34 = shorter

2 6.7 6.6 27 21 Heavy bleeding Less freq

3 7.0 7.6 14 25 More bleeding Less freq en severe

4 8.8 7.9 16 9.7 More bleeding =

5 5.1 4.5 34 30 Severe bleeding, transfusion

Less severe, wholeday bleeding

6 9.1 9.0 23 163 More bleeding less Iron IV before last Hb/ferritin

7 7.9 7.8 15 13 Some bleeding Less

8 8.8 6.9 12 5.3 More bleeding Less

Mean 7.55 7.25 19.5 23 (21)

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Video before and after treatmentNo 4-5-8

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-Meer bloedneuzen tijdens gebruik neusspray(7)-Misselijkheid tijdens gebruik neusspray(1)-Moeheid(1)

-Ernstige bloeding warvoor opname en bloedtransfusie (1)

Ernstige bijwerkingen

Bijwerkingen

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Conclusies

•Mening van de patiënt:- Tijdens de behandeling ervaarden 7/8 patienten meer bloedingen - Na behandeling ervaarden 6/8 patientsen minder of minder ernstige bloedneuzen

•Dagboek evaluatie: - Overall minder vaak en kortere duur bloedneuzen- Geen verschil in ernst bloedarmoede en ijzervoorraad - Geen relatie tussen behandelresultaat en mutatie HHT1 of HHT2

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Discussion

Application of bevacizumab: - Competence/execution of spray- Spray type: lesions?

-Dose of Bevacizumab- Previous reports: 25-100mg- This report 70mg

-Follow up- Previous effects: after one week (case report), evaluation after 2-18 months- Extra follow-up planned after 2 and 4 months use

-Adverse events: - Patient 5 stopped using thalidomide 5 weeks before treatment

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Bevacizumab Nasal Spray for Frequent Epistaxis in HHT, a pilot treatment

•Previous reports: positive effect

•Our treatment:

- Some positive signs - Problems during application

- More research needed- Study group size- Effective dose- Application- RCT- Long term effects

NOSE:- Efficacy and safety

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