1 / 31

Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie

REFRACTORY MYASTHENIA GRAVIS AND RITUXIMAB: LONG TERM FOLLOW-UP OF 3 PATIENTS AND THE “FORCE” TRIAL. Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie Hôpital Pitié-Salpêtrière, Paris, France. Stem cells. Pro-B cells.

paco
Télécharger la présentation

Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. REFRACTORY MYASTHENIA GRAVIS AND RITUXIMAB: LONG TERM FOLLOW-UP OF 3 PATIENTS AND THE “FORCE” TRIAL Olivier BENVENISTE , Bruno EYMARD Médecine Interne, Centre de Référence Maladies Neuromusculaires, Institut de Myologie Hôpital Pitié-Salpêtrière, Paris, France

  2. Stem cells Pro-B cells Pre-B cells Immature B cells Activated B cells Memory B cells Plasma B cells CD10 CD19 CD20 Cell-surface antigens CD24 CD38 CD39 Rituximab(1986) murine antibody fragment IDEC-2B8 human IgG and κ-constant regions

  3. Rituximab in oncology • Rituximab: first mAb for B lymphoma (CD20) • Dose : 375 mg / m2 • Mono therapy, once a week, 4 times. • In association (CHOP), 8 times every 21 days, • More than 1 million treated patients • Few side effects • Progressive multifocal leukoencephalopathy Czuczman et al, 1999; Hainsworth et al, 2002; Leget & Czuczman, 1998, McLaughlin et al, 1999 Smolen et al, ARD 2006; 1-8 ~ 60 cases

  4. Rituximab in autoimmune diseases N Engl J Med, 2004 • Dose: 1g, x2 • Refractory SLE • Refractory vasculitis (cryoglobulin or ANCA) • Pemphigus • Idiopathic thrombocytopenia purpura… Off-label but authorized

  5. IgG monoclonale Chaîne lambda

  6. Rituximab, 375 mg/m2, S0, S1, S2 and S3 with IVIg

  7. Ms H, 37 y. o., MG story • 1987: ptosis, diplopia and muscle fatigue. Anti-AChR +. Treated by pyridostigmine • 1988: Thymectomy, then start of prednisone • 1988-1990: Corticosteroids dependence, start of azathioprine • 1990 – 2000: Honey moon… • 2000: pharyngeal flair, start of IVIg, good response but transient • Dec 2003: first hospitalization in ICU (15 days with invasive ventilation). Prednisone (1 mg/kg/d) + azathioprine + methotrexate • Jan 2004: 2nd ICU, plasma exchanges • Feb 2004: stop azat and MTX for ciclosporine • Apr 2004 – March 2005: IVIg monthly

  8. March 2005 • Evaluation: • Myasthenic Muscle Score (MMS): 30/100 • MGFA class IVb • Great difficulties in daily life (working…) • Nasal voice, 100 ml of water: 25 s. and leaks • Anti-AChR: 140 nM/L • Decision: • 4 plasma exchanges (Anti-AChR: 10 nM/L) • Rituximab, 375 mg/m2, 4 injections (21/03/05 to 14/04/05) • IVIg

  9. Follow-up IVIg IVIg ciclo MFM Azat rituximab x2 Prednisone 110 nM/L HACA -

  10. Ms I, 37 y. o., MG story • 1999: falls and muscle fatigue. Anti-AChR +. Treated by pyridostigmine • 2000: auto-immune neutropenia and anemia • 2001: Thymectomy • 2002: MMS: 75, PN cells: 277/mm3, Hb: 9.2 g/dL ANA + (1/320) with anti-DNA Abs (54 U) => start of prednisone (50 mg/d). • Jan 2003: MMS: 60, start of Azathioprine • Nov 2003: PN cells < 300, stop for MFM but digestive intolerance, start of IVIg • Feb 2004: discoid lupus • May 2005: MMS 60, => start of rituximab (375 mg/m2, x4) after 3 Plasma Exchanges

  11. Follow-up Azat IVIg rituximab 17 nM/L

  12. Mr C, 60 y. o., MG story • 2001: ptosis and muscle fatigue. Anti-AChR Abs +. Treated by pyridostigmine • Aug 2001: Start of prednisone, Azathioprine and IVIg • 2002: MMS: 69 • Sept 2005: MMS: 40, restart of IVIg • Nov 2005: MMS: 40, start of mycophenolate mofetil and plasma exchange • Nov 2005 to April 2006: plasma exchange monthly • April 2006: start rituximab (1g, x2)

  13. Follow-up MMF rituximab 9 nM/L

  14. For how long persist the effects of rituximab? M Dalakas, Nat Clin Pract Neurol, 2008 In trials for RA : 9 months in average

  15. Rituximab and relapse C. Popa et al. Experience with repeated B-cell depletion therapy in RA suggest that ~80% of patients may respond and 50-60% become susceptible to continuing control of the disease.

  16. Human Anti-Chimeric Abs (HACA) and rituximab

  17. Patients with human antichimeric antibody (9.2%) did not exhibit decreasing efficacy or present additional safety concerns.

  18. Can rituximab decrease Ig levels ? C. Popa et al.

  19. And Abs ? N=17 N=16 C Lindholm, J Rheumatol, 2008 KG Smith, Arthritis, 2006

  20. Blood. 2004; 103:4424-8 . • Behavior of factor VIII inhibitor titers in • Patients with a continuous sustained response • Relapsed patients • Nonresponders

  21. MG and rituximab PubMed November 2009 • 11 papers: case reports or short series of patients • 13 patients AChR + • 16 patients MuSK + • 3 seronegative MG K Stieglbauer, J Neurol Sci, 2009

  22. MuSK K Stieglbauer, J Neurol Sci, 2009

  23. I Illa, J Neuroimmunol 2008

  24. I Illa, J Neuroimmunol 2008 J Diaz-Manera, Nat Clin Pract Neurol, 2007

  25. N Zebardast, Muscle Nerve, 2009

  26. Conclusions, perspectives for MG • Only retrospective case reports published • Rituximab seems effective in refractory MG • From 1 to 4 month after the first injection • The effects persist over 6 – 12 months • Patients can be retreated • Waiting for relapse? • Systematical pre-emptive retreatment? • Which dose: complete cycle or 1g only? • Rituximab can decrease the Ab titers • More frequently/rapidly for MuSK / AChR? • Rarely to an undetectable level • 4. Interest in the follow-up of the B cell count (CD19) • No relapse when CD19 remains undetectable… • Need of prospective trials

  27. Rituximab for the treatment of refractory myasthenia gravis (FORCE) Phase II, open, multicentric, prospective study. Reference ClinicalTrial.gov: NCT00774462 Funded by: APHP and AFM Rituximab given by: Roche Principal investigator: O. Benveniste Number of enrolled patients: 11 / 12

  28. Inclusion criteria • 1. Generalised MG • Severe generalised MG, MGFA class IVa, IVb or V • AchR + • 2. Refractory to the conventional treatments • - Resistance to corticosteroids, azathioprine, mycophenolate mofetil, ciclosporine, methotrexate, cyclophosphamide, IVIg and/or plasma exchange. • At least 3 (or more) of these drugs must have been tested. • During > 1 year.

  29. Schedule V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 W-4 to W-1 D-1 D0 D1 M6 M12 M18 D7 D14 D21 1st injection 2nd injection 3rd injection Rituximab: 1000 mg

  30. Outcomes • 1. Main primary: quantitative MG score at M12 • MM Score (range 0-100) • QMG Score (range 0-39) • 2. Secondary • - MG scores at M6 and M18 • MGFA postintervention status • Number of crisis per year • Forced Vital Capacity • Burden of the associated immunosuppressive drugs • Quality of life (SF36) • AChR titer • B cell reconstitution

  31. Acknowledgments Pr Hatron Pr Hachulla Number of enrolled patients: 11 / 12 Pr Levesque Pr Marie Pr Eymard Dr Bolgert Pr Annane Pr Gajdos Pr Sharshar Dr Friedman Pr Farge Pr Rousset Pr Pouget Dr Salort-Campana

More Related