Rituximab e Polineuropatie da

anticorpi anti-MAGanticorpi anti-MAG

Dott.ssa Luana Benedetti

U.O Neurologia Osp.Sant’Andrea La Spezia

Università di Genova

Polineuropatia da Ab anti-MAG

1. 80% associata MGUS Ig M, 20% M. Waldenstrom

2. +++ uomini; età 60-70 aa

3. Andamento lento progressivo ma invalidante3. Andamento lento progressivo ma invalidante

4. +++ sensitiva; interessamento motorio compare tardi

5. ENG: demielinizzante; TLI < 0.25

6. Patogenesi: IgM dirette contro la MAG

7. Biopsia nervo: slamellamento guaine mieliniche

Depositi Ig M a livello guaine mieliniche

IF indiretta

Microscopio

elettronico

Terapia delle polineuropatie da Ab anti-MAG

• Plasmaferesi

• Immunoglobuline e.v

• Interferone alfa

• Ciclosporina

RITUXIMAB

Anticorpo monoclonale chimerico anti CD20

MECCANISMO D’AZIONEMECCANISMO D’AZIONE

CD 20CD 20

Department of Neurosciences, Ophthalmology and Genetics, University of Genova

Department of Neurosciences, University of Padova

Department Neurological Sciences, Ospedale Maggiore Policlinico, Milano

Neurologia I, Department of Neurosciences, A.S.O. San Giovanni Battista, Torino

Neuromuscolar Diseases Unit, Ce.S.I, Foundation University “G. D’Annunzio”, Chieti

Department Neurological Sciences, IRCCS Humanitas Clinical Institute, Milano

JJournal Peripheral Nervous System Jun 2007;12:102-107

Clinical/Scientific Notes Neurology 2008, 71:1742-1744

Long-term effect of Rituximab in anti-MAG polyneuropathy

L. Benedetti, C. Briani, D. Franciotta, M. Carpo, L. Padua, G. Zara, R. Zambello, M.P Sormani, GL. Mancardi, E.Nobile-Orazio, A. Schenone

Clinical/Scientific Notes Neurology 2008, 71:1742-1744

Long-term effect of Rituximab in anti-MAG polyneuropathy

L. Benedetti, C. Briani, D. Franciotta, M. Carpo, L. Padua, G. Zara, R. Zambello, M.P Sormani, GL. Mancardi, E.Nobile-Orazio, A. Schenone

Risultati relativi al trattamento di 26 pazienti.

Follow-up 12 mesi

1° parte della presentazione

Risultati del follow-up a 36 mesi

2° parte della presentazione

Risultati relativi al trattamento di 26 pazienti.

Follow-up 12 mesi

1° parte della presentazione

JJournal Peripheral Nervous System Jun 2007;12:102-107

Patients

Age Disease duration

IgM Anti-MAG Ab

MRC ISS INCAT Ulnar VCM

Ulnar DML

� 26 affected by anti-MAG polyneuropathy

� 16 M, 10 F

� 20 affected by MGUS, 6 by malignant hematological disease

duration Ab VCM DML

Min 44 0.5 164 1/

1600

46 3 1 12 3.9

Max 73 16 1900 1/

12800000

60 15 8 59.2 14.5

Median 62 8 511 1/

51200

56.50 9 3 35 6

1. Treatment: Rituximab 375 mg/sqm/week x 4 weeks

• MRC Sum Score

• INCAT Disability Scale

• Ig M levels

• CD 19+ B-cells

Immunological evaluation Clinical and electrophysiological evaluation

Methods

2. Evaluation

• INCAT Disability Scale

• ISS- INCAT Sensory Scale

• MCV, DML ulnar, peroneal nerve

• CD 19+ B-cells

• Anti-MAG Ab titers

3. Statistical analysis

Wilcoxon test

Non parametric Spearman rank correlation coefficient

Quality of life (QoL): SF-36

IMMUNOLOGICAL RESULTS

CD19+ B-cells

8

10

12

14

% B

-cel

l CD

19+

CD19+ B-cells were undetectable after one month and returned to pre-treatment values after 9-12 months

0

2

4

6

0 1 3 6 12

months

% B

-cel

l CD

19+

IMMUNOLOGICAL RESULTS

IgM Anti-MAG

Significant reduction of 33% (p<0.001) Significant reduction of 81% (p=0.001)

Baseline 12 months Baseline 12 months

CLINICAL RESULTS

MRC ISS

Significant improvement of 3% (p=0.03)Significant improvement of 20% (p=0.008)

INCAT

Significant improvement of 6% (p=0.05)

� 16 pt (62%) improved in at least 2 scales

� 6 (23%) were unchanged

� 4 (15%) worsened in at least 2 scales

ELECTROPHYSIOLOGICAL RESULTS

• MCV >10% on peroneal nerve in 27% pt, on ulnar nerve in 35% pt

• DML >10% on peroneal in 88% pt, on ulnar nerve in 42% pt

� Significant improvement of 25% (p=0.001) in peroneal DML

� Significant improvement of 7% (p=0.05) in ulnar DML

� Significant improvement of 3.3% (p=0.012) in ulnar MCV

INCAT improvement correlates with. . .

MRC improvement

ISS improvement

R=-0.4, p=0.04 R=0.6, p=0.001

INCAT improvement correlates with. . .

IgM improvement

Anti-MAG title improvement

R=0.65.4, p<0.001 R=0.44, p=0.02

INCAT improvement correlates with. . .

Ulnar MCV improvement

R=-0.3.4, p=0.05

RISULTATIFattori che influenzano la risposta

-0,2

0

0,2

0,4

% IS

S c

han

ge

Il miglioramento clinico correla in modo significativo con un più basso titolo di Ab anti-MAG al baseline

-0,8

-0,6

-0,4

Ab anti-MAG baseline (log scale)

% IS

S c

han

ge

R=0.67, p=0.03

RISULTATIFattori che influenzano la risposta

1. Durata di malattia: R= 0.4, p=0.16

2. Livello Ig M al T0: R= 0.6, p=0.08

3. VCM al T0: R= -0.5, p=0.2

4. cMAP al T0: R= -0.6, p=0.07

Buoni indici di correlazione ma non raggiungono significatività

Basso n° pazienti trattati ?

RISULTATI

EFFETTI COLLATERALI

1. Un pz cefalea, regredita rallentando velocità di infusione

2. Un pz brivido, regredito con terapia 2. Un pz brivido, regredito con terapia steroidea

3. Un pz lieve, transitoria e reversibile leucopenia

4. No eventi avversi maggiori

Risultati del follow-up a 36 mesi

2° parte della presentazione

Clinical/Scientific Notes Neurology 2008, 71:1742-1744

Long-term effect of Rituximab in anti-MAG polyneuropathy

L. Benedetti, C. Briani, D. Franciotta, M. Carpo, L. Padua, G. Zara, R. Zambello, M.P Sormani, GL. Mancardi, E.Nobile-Orazio, A. Schenone

Clinical/Scientific Notes Neurology 2008, 71:1742-1744

Long-term effect of Rituximab in anti-MAG polyneuropathy

L. Benedetti, C. Briani, D. Franciotta, M. Carpo, L. Padua, G. Zara, R. Zambello, M.P Sormani, GL. Mancardi, E.Nobile-Orazio, A. Schenone

Long-term follow-up

12 patients

2 Non Responders

Retreated

0 6 12 24 36

1

2

44

48

52

56

60

0 6 12 24 36

1

2

1/64000001/1600000

1/512001/800000

1/25600

Ab anti-MAG MRC

*

*

Non responder patients to the 1st cycle and retreated

0 6 12 24 36

months months

0

2

4

6

8

10

12

14

16

18

0 6 12 24 36

months

1

2

012345678

0 6 12 24 36

months

1

2

* Retreatment at 12 month. There was progressive worsening in all scales

ISS INCAT

**

Long-term follow-up

12 patients

2 Non Responders

Retreated

10 Responders

Pt(sex,age)MRC INCAT ISS

T0 T12 T24 T36 T0 T12 T24 T36 T0 T12 T24 T36

1 (M, 48) 58 60 60 58 3 0 0 3 7 3 3 6

2 (M, 66) 54 56 50 50 4 3 6 6 12 12 16 16

3 (F, 64) 58 59 59 47 3 3 2 4 11 10 6 12

4 (F, 73) 58 60 60 60 2 1 1 1 8 2 2 2

Responder Patients

4 (F, 73) 58 60 60 60 2 1 1 1 8 2 2 2

5 (F, 57) 59 60 60 60 3 2 2 2 9 6 6 6

6 (M, 69) 59 60 60 60 2 1 1 1 10 5 5 5

7 (M, 70) 60 60 60 60 1 0 0 0 4 2 2 2

8 (M, 66) 46 50 54 54 8 7 4 4 9 8 5 5

9 (M, 82) 51 55 55 55 5 4 5 5 10 10 12 12

10 (F, 63) 56 59 59 59 4 2 2 2 7 6 6 6

Pt(sex,age)MRC INCAT ISS

T0 T12 T24 T36 T0 T12 T24 T36 T0 T12 T24 T36

1 (M, 48) 58 60 60 58 3 0 0 3 7 3 3 6

2 (M, 66) 54 56 50 50 4 3 6 6 12 12 16 16

3 (F, 64) 58 59 59 47 3 3 2 4 11 10 6 12

4 (F, 73) 58 60 60 60 2 1 1 1 8 2 2 2

Responder Patients

4 (F, 73) 58 60 60 60 2 1 1 1 8 2 2 2

5 (F, 57) 59 60 60 60 3 2 2 2 9 6 6 6

6 (M, 69) 59 60 60 60 2 1 1 1 10 5 5 5

7 (M, 70) 60 60 60 60 1 0 0 0 4 2 2 2

8 (M, 66) 46 50 54 54 8 7 4 4 9 8 5 5

9 (M, 82) 51 55 55 55 5 4 5 5 10 10 12 12

10 (F, 63) 56 59 59 59 4 2 2 2 7 6 6 6

Long-term follow-up

12 patients

2 Non Responders

Retreated

10 Responders

6 No retreated

55

56

57

58

59

60

61

0 6 12 24 36

months

1

2

3

4

5

6

Responder patients at 1st cycle, fw-up 36 months

0 6 12 24 36

months

1

2

3

4

5

6

1/200000

1/51200

1/64001/3200

1/1000

Ab anti-MAG MRC

<1/1000

months

0

2

4

6

8

10

12

0 6 12 24 36

months

1

2

3

4

5

60

1

2

3

4

5

0 6 12 24 36

months

1

2

3

4

5

6

months

ISS INCAT

4/6 increase anti-MAG Ab at 24 month. 6/6 clinical stability at 36 months

Long-term follow-up

12 patients

2 Non Responders

Retreated

10 Responders

4 Retreated for relapse

2 at month 24 2 at month 36

6 No retreated

0 6 12 24 36

months

1

2

3

4

48505254565860

0 6 12 24 36

1

2

3

4

Responders at 1st cycle, retreated x relapse

1/8000001/4000001/200000

1/512001/100000

1/256001/128001/6400

anti-MAG Ab MRC

monthsmonths

0

2

4

6

8

10

12

14

16

18

0 6 12 24 36

months

1

2

3

4

0

1

2

3

4

5

6

7

0 6 12 24 36

months

1

2

3

4

Patients were retreated at 36 month with beneficial results

ISS INCAT

LONG-TERM (36 months) RESULTS

1. Clinical improvement persisted in 6 patients2. 4 patients relapsed at months 24-36

CLINICAL RESULTS

IMMUNOLOGICAL RESULTS

1. IgM levels remained decreased by ~60% (p=0.005)2. Anti-MAG titers were still reduced by ~70% (p=0.12)3. but in 8 pt, anti-MAG Ab raised during the fw-up

Pt with relapse vs pt without relapse

1. All the 4 patients who relapsed had baseline anti-MAG titres ≥1/100,000 (median 100,000 ± 175,000)

2. none of the others had titres higher than 1/51,200 (median 27200 ± 10875, Mann-Whitney test, p=0.009)

Quality of life. SF-36

Wilcoxon Test

N T Z p-level

phy fun & phy fun 7 0,00000 2,201398 0,027709

rol phy & rol phy 7 0,00000 2,201398 0,027709

bod pain & bod pain 7 0,00000 2,366432 0,017961

gen hea & gen hea 7 0,00000 2,366432 0,017961

QoL assessment

showed significant

improvement of gen hea & gen hea 7 0,00000 2,366432 0,017961

vit & vit 7 0,00000 2,366432 0,017961

soc fun & soc fun 7 0,00000 2,366432 0,017961

rol emo & rol emo 7 0,00000 2,201398 0,027709

men hea & men hea 7 0,00000 2,366432 0,017961

phy com sc & phy com sc 7 0,00000 2,366432 0,017961

men com sc & men com sc 7 0,00000 2,366432 0,017961

improvement of PCS and MCS

at follow-up (both p=0.02).

CONCLUSION (1)

• CD19+ B-cells were undetectable after 1 month, reappeared after 9-12 months

• Significant reduction of IgM levels (33%) (p<0.001)

• Significant reduction of anti-MAG Ab (81%) (p=0.001)

Immunological results

Patients: 26Follow-up: 12 months

Clinical results

� 16 pt (62%) improved in at least 2 scales

� 6 (23%) were unchanged

� 4 (15%) worsened in at least 2 scales

The % of responders (62%) was the similar of that previously reported

66% Renaud et al. Muscle&Nerve 2003; 75% Dalakas et al. Ann Neurol 2006

(80%) showed clinical stability for 24 months

(60%) showed clinical stability for 36 months

1. In non-responder patients . . . Retreatment was not useful

4. Responder patients can remain stable for a long time

CONCLUSION (2) Long-term follow-up

Garcia-Chavez J et al. Ann Hematol 2007

2. Responder patients can present a clinical or immunological relapse

4. A single rituximab course may induce QoL benefit

5. The 1st and 2nd treatment were safe:no major adverse effects were reported

In 8/10 Anti-MAG Ab increased after 24 months

In 4 patients there was a clinical relapse

3. In responder patients with relapse. . . Retreatment was useful

Based on our results:

SPECULATIONS� Clinical improvement correlated with lower anti-MAG Ab titers at baseline

� Clinical deterioration in responder pt correlated with both high baseline anti-MAG titres and their increase during follow-up

Based on our results:

1. Rituximab may be particularly effective in

patients with low antibody titre and in the early

course of the disease

2. Patients with baseline very high anti-MAG titre

may require additional rituximab courses, both as

induction and as maintenance therapy.

Zaja F et al. Exp Hematol 2006

Renaud S et al. Neurology 2006

GRAZIE

PER PER

L’ATTENZIONE