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Gil I. Wolfe, MD Dept. of Neurology

Thymectomy in Non-thymomatous MG: Results from MTGX, a Randomized, Controlled Trial MSG Scientific Annual Meeting Sept 2016, Snowbird, UT. Gil I. Wolfe, MD Dept. of Neurology Univ. at Buffalo/SUNY Jacobs School of Medicine and Biomedical Sciences Buffalo, NY. U01 NS042685.

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Gil I. Wolfe, MD Dept. of Neurology

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  1. Thymectomy in Non-thymomatous MG: Results from MTGX, a Randomized, Controlled Trial MSG Scientific Annual Meeting Sept 2016, Snowbird, UT Gil I. Wolfe, MD Dept. of Neurology Univ. at Buffalo/SUNY Jacobs School of Medicine and Biomedical Sciences Buffalo, NY U01 NS042685

  2. The Thymectomy Dilemma 1) Why? 2) How? (MGTX trial) 3) What? (MGTX trial results)

  3. The Thymectomy Dilemma 1) Why?

  4. Thymectomy for non-thymomatous MG • Historical aspects • Blalock et al. JAMA 1941;117:1529-1533 • Sustained remission in initial patient with cystic thymic tumor (Blalock et al. Ann Surg 1939;110:544-561) • Removal of entire thymus gland from mediastinum in 6 patients without thymoma • 1 pt symptom-free • 2 pts significantly improved • 2 pts slightly improved • 1 death from pulmonary complications • No Class I evidence for over 70 years

  5. Thymectomy for MG • Non-thymomatous MG • Consensus in favor of thymectomy • Based on non-randomized case series • Repeated calls for randomized, controlled studies • Gronseth & Barohn, 2000 (Neurology 55:7) • Grob, 1981 (comments in Ann NY Acad Sci 377:764) • McQuillen & Leone, 1977 (Neurology 27;1103) • Trial efforts failed in 1963, 1980, early 1990s

  6. Lifetime Course of MGGrob et al. Muscle Nerve 2008;37:141David Grob, MD, 1919-2008 Transsternalthymectomy effect on remission • 1940-57 • Significant effect (20% vs. 10%) • 1958-1967 • Similar remission and improvement rates • 1966-2000 • Slightly higher mortality and lower remission rates in thymectomy group P values vs. 1940-57

  7. Non-thymomatous MG • Evidence-based AAN Practice Parameter • Gronseth & Barohn. Neurology 2000;55:7 • 28 Class II studies (controlled, non-randomized) • 21 MG cohorts • 4136 surgical pts • 4354 non-surgical pts • Published between 1953-1998 • Majority used transsternal approach • Mean f/u range 3-28 years • No blinded assessments

  8. Non-thymomatous MG AAN Practice Parameter Gronseth & Barohn. Neurology 2000;55:7

  9. AAN Practice Parameter • Conclusions and recommendations • Benefit of thymectomy not established conclusively • More effective in generalized, severe, female patients? • Recommended as treatment option • Controlled trial needed • Standardized medical therapy for all arms • Defined outcome measures • Compare different surgical approaches • Gronseth & Barohn. Neurology 2000;55:7

  10. The Thymectomy Dilemma 1) Why? 2) How?

  11. MGTX and BioMG Executive Committee John Newsom-Davis, MD (Study Chair, emeritus) Gary Cutter, PhD (Director, DCC, UAB) Gil Wolfe, MD (Study Chair) Henry Kaminski, MD (Study Vice Chair; Director BioMG) Inmaculada Aban, PhD (Deputy Director, DCC) Alfred Jaretzki, MD (Surgical Chair, emeritus) Joshua Sonnett, MD (Surgical Chair) Greg Minisman (Project Manager) Robin Conwit, MD (NINDS Program Director) Joanne Odenkirchen, MPH (NINDS colleague) 1932-2007 U01 NS042685 1919-2014

  12. MGTX: Single blind, Multicenter, International Randomized Trial • Primary aim: Answer 3 questions in non-thymomatous MG patients followed for 3 years • Compared with prednisone protocol alone, does extended transsternalthymectomy (ETTX) + prednisone protocol • result in: • greater improvement in strength (time-weighted average QMG)? • lower prednisone requirement (time-weighted average prednisone dose)? • enhanced quality of life (AEs, TAS, TAC)?

  13. MGTX protocol details Inclusion criteria AChR binding Ab pos (≥0.5) MGFA Class 2-4; disease duration < 5 years Age at least 18 and < 65 years Optimal anti-cholinesterase dose Prednisone naive or not Main exclusion criteria Previous thymectomy or sternotomy or thoracotomy Immunosuppressive therapy (x prednisone) within last year Rituximab at any time Medically or psychiatrically unfit for thymectomy Chest CT or MR evidence of thymoma Pregnancy or lactation, or considering becoming pregnant Current prednisone > 0.75 mg/kg or 50 mg/d (or ADequivalent)

  14. MGTX Trial 67 sites in N. America, Europe, S. America, S. Africa, Asia, Australia AChRAb+, MGFA Clinical Class II-IV, ≤5 yrs, no thymoma, 18-65 yo, +/- prednisone Rx ETTX + Prednisone 1.5 mg/kg AD randomize Prednisone alone1.5 mg/kg AD MMS: prednisone taper MMS: prednisone taper 1° Time-weighted QMG & Prednisone, AEs at 3 yrs 2° MMS MG-ADL ∆SF-36 Hospital days 1° Time-weighted QMG & Prednisone, AEs at 3 yrs 2° MMS ∆MG-ADL ∆SF-36 Hospital days outcome measures

  15. MGTX protocol details • Dual primary outcome • Clinical response (Time-weighted QMG) • Blinded evaluator (BE) • Prednisone requirements (Time-weighted AD prednisone) • If primary outcome ambiguous • Serious adverse events/TAC/TAS • Prednisone dosing based on Minimal Manifestation Status (MGFA) • No symptoms or functional limitations from MG but some weakness present on careful examination • Jaretzki et al. Neurology 2000;55:16 • QMG score <14; ≤ baseline value • Treatment options • Azathioprine or other IS agent allowed • if MMS not reached by 1 year OR • severe prednisone-related AEs via protocol deviation

  16. Investigator PredictionsPrior to Starting the Trial

  17. MGTX Results 1) Why? 2) How? 3) What? Wolfe GI et al. N Engl J Med 2016;375:511-522

  18. Rate of Recruitment

  19. MGTX: n=126 Refusals ITT analysis

  20. Demographic and Baseline Clinical Characteristics of MGTX Subjects

  21. QMG Score (Mean±SE) by Treatment Group QMG difference: 2.85 pts (99.5% CI 0.47-5.22; p<0.001)

  22. AD Prednisone Dose (Mean±SE) by Treatment Group Time weighted average prednisone dose difference: 44 mg vs 60 mg (95% CI 7-25 mg; p<0.001)

  23. Primary and Subgroup Analyses

  24. Secondary Analyses

  25. Summary of Adverse Events † Disability/incapacity etiologies: for prednisone alone group, worsening swallowing difficulties and myasthenia gravis; in thymectomy+prednisone group, osteoporotic thoracic fracture, ocular muscle involvement due to relapsing MG, post-thymectomy diaphragmatic hemiparesis, rib fracture, impending myasthenic crisis, Pott’s fracture, tear of left knee meniscus, and low back pain with possible stenosis. MEDRA denotes medical dictionary for regulatory activities, MG myasthenia gravis.

  26. Treatment-associated symptoms • Patients with ≥ 1 symptom • p=0.22 over 0-12 months • p=0.002 over 0-24 months • p<0.001 over 0-36 months • Mean no. of symptoms • p=0.007 over 0-12 months • p=0.02 over 0-24 months • p<0.001 over 0-36 months • Mean distress level (0-4, “not at all” to “extremely”) • p=0.04 over 0-12 months • p=0.003 over 0-24 months • p=0.003 over 0-36 months • Treatment-associated complications and SF-36 without significant differences

  27. Thymic Histology from 46 Patients Randomized to ETTX 67% of specimens with TFH aThymic follicular hyperplasia was defined by counting CD23+ follicular dendritic cell networks and graded as: Grade 0, no follicles; Grade 1, follicles in ≤1/3 of thymic lobules; Grade 2, follicles in >1/3 and ≤ 2/3 of thymic lobules; Grade 3, follicles in >2/3 of thymic lobules; Grade 4, lymph node-like transformation of the thymus with >4 follicles per low power field (x50 magnification). One patient found to have WHO type B2 thymoma (excluded from above)

  28. BioMG • Analysis of thymus samples • Standard operating and handling procedures working well • Well suited for biomarker studies • Grading system for lymphofollicular hyperplasia to be correlated with clinical data • Marx et al. Ann NY AcadSci2012;1275:92

  29. MGTX in ContextStatements for non-thymomatous MG • Cochrane Collaboration • “There is no randomized controlled trial literature that allows meaningful conclusions about the efficacy of thymectomy on MG. Data from several class III observational studies suggest that thymectomy could be beneficial in MG. An RCT is needed…” • Cea G, et al. Cochrane Library 2013;10:1-20 • Intl MG Treatment Recommendations • “In non-thymomatous MG, thymectomy is performed as an option to potentially avoid or minimize the dose or duration of immunotherapy, or if patients fail to respond to an initial trial of immunotherapy or have intolerable side effects from that therapy.” • Sanders DB, Wolfe GI, Benatar M, et al. Neurology2016; 87:419-425

  30. MGTX Summary • Class I evidence: ETTX has favorable impact on AChRAb+ generalized MG • Clinical outcomes • Corticosteroid exposure • Adverse events • Effect can be seen in <12 months • Future investigations • Predictive role of thymic histology • BioMG: Genomic/proteomic profiles, biomarker assessments Wolfe GI et al. N Engl J Med 2016;375:511-522

  31. Many Thanks! March 2006 San Fran / Oxford Study subjects: Trust in randomization; ≥3 yrs MGTX Investigators/DSMB

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