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:
Sustained remission in initial patient with cystic thymic tumor (Blalock et al. Ann Surg 1939;110: )
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 MG Grob et al
Lifetime Course of MG Grob et al. Muscle Nerve 2008;37:141 David Grob, MD,
Transsternal thymectomy effect on remission
Significant effect (20% vs. 10%)
Similar remission and improvement rates
Slightly higher mortality and lower remission rates in thymectomy group
P values vs

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
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 U01 NS042685
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)
U01 NS042685

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 transsternal thymectomy (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 Main exclusion 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 AD equivalent)

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, yo, +/- prednisone Rx
ETTX Prednisone 1.5 mg/kg AD
randomize
Prednisone alone 1.5 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 If primary outcome ambiguous
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 Predictions Prior to Starting the Trial

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

18. Rate of Recruitment

19. MGTX: n=126
Refusals
ITT analysis

20. Thymectomy+prednisone
Demographic and Baseline Clinical Characteristics of MGTX Subjects
Characteristic
Prednisone Alone
(N=60)
Thymectomy+prednisone
(N=66)
Gender – no. (%)
Female
39 (65)
50 (76)
Ethnicity – no.(%) 
Asian
4 (7)
6 (9)
Black/African American
6 (10)
7 (11)
Hispanic
17 (28)
17 (26)
White, not Hispanic origin
30 (50)
31 (47)
Other (Mixed/Native American/Alaskan)
3 (5)
5 (8)
Therapy at enrollment* – no (%)
Pyridostigmine
56 (93)
60 (91)
Corticosteroids
47 (78)
49 (74)
Prior intravenous immunoglobulin
13 (22)
12 (18)
Prior plasma exchange
7 (12)
9 (14)
MG Foundation of America Class† – no.(%)
Class IIa
25 (42)
25 (38)
Class IIb
14 (23)
18 (27)
Class III
20 (33)
21 (32)
Class IV
1 (2)
2 (3)
Median age in years (min-max)
33.0 ( )
32.0 ( )
Median disease duration in years (min-max)
1.14 ( )
1.08 ( )
Quantitative MG score‡: Mean ± SD
12.35 ± 4.90
11.40 ± 5.12
Prednisone dosage (mg): Mean ± SD
42.49 ± 23.52
43.43 ± 28.92

21. QMG Score (Mean±SE) by Treatment Group
QMG difference: 2.85 pts (99.5% CI ; 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
Treatment Group
Mean±SD
Estimated
Difference
(95% CI†)
P Valuea
Prednisone
alone
Thymectomy+
prednisone
Primary Analyses
Time-weighted average
Quantitative MG score
8.99 ± 4.93 (N=56)
6.15 ± 4.09 (N=62)
2.85 ( )
< 0.001
alternate-day prednisone dose (mg)
59.8 ± 27.4 (N=56)
43.6 ± 21.2 (N=61)
16.2 ( )
Subgroup Analyses
Time-weighted average Quantitative MG score
Prednisone use at enrollment (interaction with treatment P valueb=0.86)
Not prednisone naїve
9.10 ± 5.06 (N=46)
6.30 ± 3.89 (N=47)
2.80 ( )
0.004
Prednisone naїve
8.84 ± 4.60 (N=9)
5.66 ± 4.79 (N=15)
3.18 ( )
0.12
Gender (interaction with treatment P valueb=0.57)
Female
9.73 ± 5.16 (N=38)
6.47 ± 4.13 (N=46)
3.26 ( )
0.002
Male
7.45 ± 4.11 (N=18)
5.23 ± 3.95 (N=16)
2.22 ( )
Age (years) at disease onset (interaction with treatment P valueb=0.74)
< 40
9.60 ± 5.32 (N=34)
6.50 ± 4.41 (N=42)
3.10 ( )
0.007
≥ 40
7.85 ± 3.50 (N=18)
5.33 ± 2.79 (N=18)
2.52 ( )
0.02
Time-weighted average alternate-day prednisone dose (mg)
Prednisone use at enrollment (interaction with treatment P valueb=0.37)
61.5 ± 28.5 (N=46)
44.3 ± 21.9 (N=46)
17.2 ( )
48.5 ± 19.0 (N=9)
41.5 ± (N=15)
7.0 ( )
0.40
Gender (interaction with treatment P valueb =0.32)
59.19 ± (N=37)
45.76 ± (N=45)
13.43 ( )
0.01
61.08 ± (N=19)
37.70 ± (N=16)
23.38 ( )
0.009
Age (years) at disease onset (interaction with treatment P valueb=0.94)
60.79 ± 27.11(N=33)
44.92 ± (N=41)
15.87 ( )
56.08 ± (N=19)
40.93 ± (N=18)
15.16 ( )
0.07

24. Secondary Analyses Method 1 = maximum dose
Treatment Group
Mean±SD or no./N (%)
Estimated
Difference
(95% CI)
P Value
Prednisone
Alone
Thymectomy
+prednisone
Time-weighted average prescribed AD prednisone dose (mg)a
59.3 ± 28.4
(N=56)
43.4 ± 23.1
(N=62)
16.0 ( )
0.001
Penalized time-weighted average AD prednisone dose (mg; max dose)a,b
72.9 ± 37.4
46.7 ± 24.9
(N=61)
26.3 ( )
< 0.001
Penalized time-weighted AD average prednisone dose (mg; dose at start)a,c
68.1 ± 38.3
45.6 ± 24.3
22.5 ( )
Time-weighted average MG
Activities of Daily Livinga,d
3.41 ± 2.58
(N=55)
2.24 ± 2.09
1.17 ( )
0.008
MG ADL at month 12
3.33 ± 3.40 (N=54)
1.92 ± 2.73 (N=61)
1.42 ( )
0.01
MG ADL at month 24
3.11 ± 2.93 (N=53)
2.02 ± 2.78 (N=59)
1.10 ( )
0.04
MG ADL at month 36
2.69 ± 2.80 (N=51)
2.14 ± 2.92 (N=59)
0.55 ( )
0.32
Azathioprine usee
28/58 (48)
11/65 (17)
31.4% (15.6%,47.1%)
Plasma exchange usee
9/58 (16)
10/65 (15)
0.1% (-12.7%,12.9%) ~1
Intravenous immunoglobulin usee
23/58 (40)
22.7% (7%,38.3%)
0.005
Minimal Manifestation Statuse
at month 12f
20/54 (37)
41/61 (67)
30.2% (12.7%-47.6%)
at month 24f
20/53 (38)
39/59 (66)
28.4% (10.6%-46.2%)
0.003
at month 36f
24/51 (47)
39/58 (67)
20.2% (1.9%-38.5%)
0.03
Hospitalization for MG exacerbation
Months 0-24: # of patientsg
17/60 (28)
6/66 (9)
19.2% (5.9%, 32.6%)
0.006
Cumulative daysh
26.4 ± 28.9
5.5 ± 2.9
0.004
Months 0-36: # of patientsg
22/60 (37)
27.6% (13.6%, 41.6%)
<0.001
22.5± 27.1
8.7 ± 7.7
0.21
Method 1 = maximum dose
Method 2 = Last dose prior to initiation of Prednison

25. Summary of Adverse Events†
Prednisone Alone
(N=60)
Thymectomy+
Prednisone (N=66)
Number of events 93 48
Patients having ≥1 event– no.(%)
33 (55)
25 (38)
Classification by patient no.(%)
Life threatening
7 (12)
1 (2)
Disability/Incapacity†
2 (3)
8 (12)
Required medical or surgical intervention
5 (8)
9 (14)
Death
0 (0)
Complication due to thymectomy
Not applicable
Hospitalization
31 (52)
15 (23)
Patients hospitalized for MG exacerbation
22 (37)
6 (9)
Mean ± SD cumulative hospital days
19.2 ± 24.5
8.4 ± 8.6
Hospitalization by MEDRA codes
Gastrointestinal disorders
Hepatobiliary disorders
Infections and infestations
4 (6)
Injury, poisoning and procedure complications
Metabolism and nutrition disorders
Nervous system disorders
Respiratory, thoracic and mediastinal disorders
Surgical and medical procedures
Vascular disorders
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 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
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
TFH (CD23+)a 15 18 6 5 2
Overall atrophy 1 7 14
Cortical atrophy 10 12 4
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 Acad Sci 2012;1275:92

29. MGTX in Context Statements 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. Neurology 2016; 87:

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:

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