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doi: 10.1111/ene.13838
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PROF. CHIARA BRIANI (Orcid ID : 0000-0001-8035-0200)
DR. ALESSANDRO SALVALAGGIO (Orcid ID : 0000-0002-1273-7566)
Article type : Short Communications
Obinutuzumab, a new anti-CD20 antibody, and chlorambucil are
active and effective in anti-MAG antibody polyneuropathy
Briani C1*, Visentin A2, Salvalaggio A1, Cacciavillani M3, Trentin L2.
1Neurology Unit, Department of Neuroscience, University of Padova. 2Hematology and
Clinical Immunology Unit, Department of Medicine, University of Padova; 3CEMES, Data
Medica Group, Padova, Italy.
*Correspondence to:
Chiara Briani, MD
Department of Neurosciences: Sciences, University of Padova
Via Giustiniani, 5, 35128 Padova - Italy
Tel.: +39-049-8213600 Fax: +39-049-8751770
E-mail: chiara.briani@unipd.it
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Keywords: Obinutuzumab, anti-MAG neuropathy, paraprotein, chronic lymphocytic
leukemia
Running title: Obinutuzumab in anti-MAG antibody neuropathy
Abstract
Background. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has been used
in polyneuropathy associated with anti-MAG antibody polyneuropathy with controversial
results.
Herein, we report on two patients with anti-MAG antibody neuropathy and concurrent
chronic lymphocytic leukemia (CLL), who dramatically responded to obinutuzumab, a novel
glycoengineered humanized anti-CD20 mAb.
Methods. Patient 1 was a 82-year-old man with severe demyelinating sensory-motor
neuropathy. He was wheelchair-bound, with loss of sensation up to knees. He had a CLL,
IgM lambda monoclonal gammopathy, anti-MAG antibodies >70,000BTU. Patient 2 was a
84-year-old women with demyelinating neuropathy, paresthesias and gait instability. She had
CLL and IgM kappa paraprotein with anti-MAG antibodies >70,000BTU. Both patients
were treated with obinutuzumab intravenously at 100mg on day +1, 900mg +2, then at
1,000mg on day 8 and 15 of cycle 1 and day 1 of cycles 2-6; chlorambucil orally at 0.5mg/kg
at day 1 and 15 of cycles 1-6.
Results. Patients 1 at cycle 6 was able to stand, gait was possible with monolateral support,
hypoesthesia and strength improved. M-protein and IgM level decreased. In patient 2 already
after 3 cycles the monoclonal component disappeared and there was dramatic improvement
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of symptoms and gait normalization. At the end to therapy anti-MAG Ab titer decreased to
5,462BTU. Neurophysiology also improved.
Conclusions. In our patients obinutuzumab was effective as first-line treatment of anti-MAG
antibody polyneuropathy. CLL might have had a role in the response to therapy, but the
associations might be considered in future trials.
Introduction.
Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has been used in
polyneuropathy associated with anti-myelin-associated-glycoprotein (MAG) antibodies with
controversial results [1]. Obinutuzumab, a novel, type II glycoengineered humanized anti-
CD20 mAb [2], in combination with chlorambucil or bendamustine, is able to induce higher
response and longer progression-free survival in chronic lymphocytic leukemia (CLL) [3], as
compared with rituximab.
We report on two therapy-naïve anti-MAG antibody neuropathy patients who had been
successfully treated with obintuzumab and chlorambucil.
Patient 1 was a 82-year-old man, who had been complaining of gait disturbances for several
years. When we first saw the patient, he used wheelchair to travel outdoors (Inflammatory
Neuropathy Cause and Treatment, INCAT leg disability score 4), was incapable of standing
and able to walk a few steps only with bilateral support. He had bilateral distal weakness
(tibialis anterior, extensor hallucis longus, gastrocnemius 2/5 MRC bilaterally), tactile
hypoestesia and loss of vibration up to the knees, areflexia, upper limbs tremor.
Neurophysiology (performed maintaining the skin temperature at 36 °C with Keypoint
Workstation Dantec, Skovlunde, Denmark) [4] showed distal demyelinating neuropathy, with
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severe secondary axonal degeneration at lower limbs (Table). The patient had a mild clonal B
lymphocytosis CD5+ CD19+ CD23+, compatible with CLL, IgM lambda monoclonal
gammopathy. Anti-MAG antibodies were >70,000BTU. Bone marrow biopsy showed a
small infiltrate of low grade lymphoma that at immunophenotype was consistent with CLL.
IGHV gene was mutated and TP53 abnormalities, deletion and mutations, were absent. The
presence of favorable prognostic CLL markers [5] and comorbidities prompt us to use
chlorambucil+obinutuzumab. Obinutuzumab was given intravenously at 100mg on day +1,
900mg +2, then at 1000mg on day 8 and 15 of cycle 1 and day 1 of cycles 2-6; chlorambucil
orally at 0.5mg/kg at day 1 and 15 of cycles 1-6. At cycle 6 the patient was able to stand, gait
was possible with monolateral support (INCAT leg disability 3), tactile hypoestesia was
limited to the feet, distal strength slightly improved (3/5 MRC), and vibration was regained at
toes. Monoclonal protein decreased from 15.8g/L to 8.46g/L. Similarly, total IgM (14.8 vs
6.7g/L), and lymphocyte (6,340 vs 900/µl) decreased. Anti-MAG antibody titer remained
stable. Two months after the end of treatment the patients died of pneumonia.
Patient 2 was a 84-year-old women with a 10 months history of painful paresthesias at lower
limbs and gait instability (INCAT leg disability 1). Neurophysiology revealed distal
symmetric demyelinating neuropathy (Table). Blood tests revealed the presence of CLL
(9,100/µL clonal B lymphocytes CD5+ CD19+ CD23+ CD200+) and IgM kappa paraprotein.
Anti-MAG antibodies were >70,000BTU. Bone marrow biopsy confirmed the presence of
15% CLL cells. Chlorambucil+obinutuzumab were administered as the same schedule as in
the first patient.
Already after 3 cycles the monoclonal component disappeared and the patient reported
dramatic improvement of symptoms and gait normalization (INCAT leg disability 0). At the
end of cycle 6 lymphocytes decreased to 1,260/mL, monoclonal component persisted absent,
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IgM 0.6g/L, anti-MAG antibodies were 5,462BTU. Neurophysiological findings also
improved (Table, Figure).
Both patients completed all the planned treatment. Both developed grade 2 neutropenia (i.e.
neutrophils count between 500-1,000/L), one reported 2 grade 3 pneumonias requiring
hospitalization and one grade 2 anemia (i.e. Hb 80-100g/l). None reported infusion-related
drug reactions.
Discussion.
Anti-MAG antibody neuropathy is a slowly progressive neuropathy, that may become
disabling when sensory ataxia worsen or motor impairment occur. Anti-MAG antibodies are
pathogenic [6], and Rituximab seems to be effective regardless of the associated
hematological disease [7]. However rituximab provides benefit only in a subgroup of
patients, and repeated cycles are often necessary with progressive loss of efficacy. We have
described two patients with anti-MAG antibody neuropathy and CLL successfully treated
with obinutuzumab-chlorambucil as first therapy. Obinutuzumab is a type II, glycoengineered
humanized anti-CD20 mAb significantly more potent than rituximab in depleting B-cells [2-
3]. In the phase III CLL11 study, 781 patients with untreated elderly CLL and comorbidities
were randomized to chlorambucil vs chlorambucil-rituximab vs chlorambucil-obinutuzumab
[3]. Chlorambucil-obinutuzumab achieved higher complete remission rate, longer progression
free survival, and improved overall survival. Both our patients developed neutropenia and
one developed a fatal pneumonia, known expected adverse events for elderly CLL patients
with comorbidities receiving chemo-immunotherapy [8].
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Rakocevic et al. recently described two patients unsuccessfully treated with obinutuzumab,
after failure or loss of efficacy of rituximab [9]. Despite loss of clinical efficacy, the authors
reported a great effect of obinutuzumab on anti-MAG antibodies titer and on IgM levels,
indicating the biological efficacy of the drug. As the authors themselves hypothesized, the
presence of axonal damage and the long history of the neuropathy might have contributed to
the little response. Also in our first patient the neuropathy had progressed to severe motor
impairment, but the clinical response at 6 months therapy was evident. Unfortunately the
patients later died of pneumonia. In patient 2, who started with less severe neuropathy, the
efficacy was clear already at the third cycle (third month) of therapy and further improved
after the sixth cycle. Also neurophysiology improved. Our data indicate that obinutuzumab-
chlorambucil may be effective in anti-MAG antibody polyneuropathy as first-line treatment,
independently of the neuropathy severity. The associated CLL might have had a role in the
response to therapy, and also chlorambucil itself might have contributed to the response [10].
Results on a wider sample of patients are however needed. Caution is warranted for potential
adverse effect in older patients.
Acknowledgements: None
Conflicts of interest and source of funding: None
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References
1. Lunn MP, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated
glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst
Rev 2016;10:CD002827.
2. Mossner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody
therapy through the engineering of a new type II anti-CD20 antibody with enhanced
direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010, 4393–
4402.
3. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of
chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015,
1602–1604.
4. Frigeni B, Cacciavillani M, Ermani M, et al. Neurophysiological examination of
dorsal sural nerve. Muscle Nerve. 2012;46:895-898.
5. Visentin A, Facco M, Frezzato F, et al. Integrated CLL Scoring System, a New and
Simple Index to Predict Time to Treatment and Overall Survival in Patients With
Chronic Lymphocytic Leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:612-
20.e1-5
6. Dalakas MC. Advances in the diagnosis, immunopathogenesis and therapies of IgM-
anti-MAG antibody-mediated neuropathies. Ther Adv Neurol Disord 2018;
15;11:1756285617746640.
7. Campagnolo M, Zambello R, Nobile-Orazio E, et al. IgM MGUS and Waldenstrom-
associated anti-MAG neuropathies display similar response to rituximab therapy. J
Neurol Neurosurg Psychiatry 2017;88:1094-1097.
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8. Visentin A, Compagno N, Cinetto F, et al. Clinical profile associated with infections
in patients with chronic lymphocytic leukemia. Protective role of immunoglobulin
replacement therapy. Haematologica 2015;100:e515–e518.
9. Rakocevic G, Martinez-Outschoorn U, Dalakas MC. Obinutuzumab, a potent anti-B-
cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy. Neurol
Neuroimmunol Neuroinflamm. 2018;5(4):e460.
10. Oksenhendler E, Chevret S, Léger JM, Louboutin JP, Bussel A, Brouet JC. Plasma
exchange and chlorambucil in polyneuropathy associated with monoclonal IgM
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Psychiatry. 1995;59:243-247.
Legend to Table: DL: distal latency; CV: conduction velocity; cMAP: compound motor
action potential; SAP: sensory action potential; BE: below elbow; AE: above elbow; BFH:
below fibular head; LPF: lateral popliteal fossa; PF: popliteal fossa; APB: abductor pollicis
brevis; ADM: abductor digiti minimi; EDB: extensor digitorum brevis; EDL: extensor
digitorum longus; TA, tibialis anterior; AH, abductor hallucis; NR: no response; R: right; L:
left; m: motor; s: sensory; TLI: terminal latency index.
Normal values: median nerve DL ≤3,5 ms; SCV ≥48 m/s; SAP ≥15 µV; MCV ≥50 m/s;
cMAP ≥6 mV; ulnar nerve DL ≤3,1 ms; SCV ≥48 m/s; SAP ≥10 µV; MCV ≥50 m/s; cMAP
≥4 mV; radial nerve SCV ≥40 m/s; SAP ≥10 µV; peroneal nerve DL ≤5,5 ms; MCV ≥40 m/s;
cMAP ≥3 mV; tibial nerve DL ≤6 ms; MCV ≥40 m/s; cMAP ≥4 mV; sural nerve SCV ≥50
m/s; SAP ≥5 µV; F-wave median/ulnar < 32 ms; F-wave peroneal < 56 ms.
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SA: spontaneous activity; Rec: recruitment; Amp: amplitude; Dur: duration; Poly:
polyphasia; N: normal; 0 absent; ++ moderate; : increased; ↓: slight reduction; ↓↓: moderate
reduction; ↓↓↓: marked reduction; NR: no motor units recruited.
Legend to Figure: left (A,C) and right (B,D) peroneal nerve conduction studies in patient 2.
To note the significant reduction of Distal Latency (clearly evident when comparing the
latency to negative peak) before (A,B) and after (C,D) therapy.
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Patient 1
Nerve conduction studies
Needle EMG
Nerve
Stimulation
site
Recording
site
DL
(ms)
CV
(m/s)
Amplitude
(cMAP=mV
SAP=µV)
Total
duration
(ms)
F
Latency
(ms)
Muscle
SA
Rec
Amp
Dur
Poly
L Median (m)
Wrist
ABP
6.43
5.6
14.8
39
L Deltoid
0
N
N
N
N
Elbow
ABP
32
4.3
17.9
R Deltoid
0
N
N
N
N
L Ulnar (m)
Wrist
ADM
4.27
4.0
13.6
41
L Biceps brachii
0
N
N
N
N
BE
ADM
35
3.6
17.1
L Triceps brachii
0
N
N
N
N
AE
ADM
32
3.4
17.3
L 1st dorsal interosseous
0
N
N
N
N
L Peroneal (m)
Ankle
EDB
NR
R 1st dorsal interosseous
0
N
N
N
N
L Peroneal (m)
BFH
TA
17.1
0.74
25.6
L Gluteus maximus
0
N
N
N
N
LPF
TA
23
0.74
27.2
R Gluteus maximus
0
N
N
N
N
R Tibial (m)
Ankle
AH
NR
L Biceps femoralis
0
N
N
N
N
PF
AH
R Biceps femoralis
0
N
N
N
N
L Median (s)
1th finger
Wrist
NR
L Vastus lateralis
0
N
N
N
N
3rd finger
Wrist
NR
R Vastus lateralis
0
N
N
N
N
L Ulnar (s)
5th finger
Wrist
NR
L Vastus medialis
0
N
N
N
N
L Radial (s)
1th finger
Wrist
NR
R Vastus medialis
0
N
N
N
N
R Sural (s)
Mild calf
Ankle
NR
L Tibialis anterior
0
↓↓↓
↓↓↓
L Sural (s)
Mild calf
Ankle
NR
R Tibialis anterior
0
↓↓↓
↓↓↓
L Extensor digitorum comunis
++
↓↓↓
↓↓↓
R Extensor digitorum comunis
++
↓↓↓
↓↓↓
L Gastrocnemius
++
↓↓↓
↓↓↓
R Gastrocnemius
++
↓↓↓
↓↓↓
L Extensor digitorum brevis
++
NR
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R Extensor digitorum brevis
++
NR
L Abductor hallucis
++
NR
R Abductor hallucis
++
NR
Patient 2
Nerve Conduction Studies
Nerve Conduction Studies, follow up
Nerve
Stimulation
site
Recording
site
DL
(ms)
CV
(m/s)
Amplitude
(cMAP=mV
SAP=µV)
Total
duration
(ms)
F
Latency
(ms)
DL
(ms)
CV
(m/s)
Amplitude
(cMAP=mV
SAP=µV)
Total
duration
(ms)
F
Latency
(ms)
L Median (m)
Wrist
ABP
15.0
2.4
17.2
49
9.52
3.3
15.6
38
Elbow
ABP
34
2.4
17.5
46
3.3
16.1
R Median (m)
Wrist
ABP
14.3
1.0
16.1
7.85
2.4
15.9
36
Elbow
ABP
37
1.4
16.1
43
2.4
16.8
R Ulnar (m)
Wrist
ADM
4.37
5.6
12.7
35
2.93
4.4
12.2
32
BE
ADM
48
5.4
13.6
53
4.4
13.0
AE
ADM
44
5.2
14.0
49
4.3
13.5
L Peroneal (m)
Ankle
EDB
8.31
2.5
15.8
79
5.73
2.5
12.9
65
LPF
EDB
30
1.7
19.3
35
1.8
21.1
R Peroneal (m)
Ankle
EDB
8.21
3.3
12.7
5.16
4.4
10.3
LPF
EDB
40
3.3
14.5
38
3.0
12.8
L Tibial (m)
Ankle
AH
11.8
0.2
27.5
9.56
0.3
15.9
PF
AH
27
0.2
29.1
35
0.3
19.4
R Tibial (m)
Ankle
AH
13.2
0.7
34.7
9.34
0.7
16.7
PF
AH
28
0.6
35.9
34
1.1
16.9
L Median (s)
1th finger
Wrist
NR
NR
3rd finger
Wrist
NR
NR
R Median (s)
1th finger
Wrist
NR
NR
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3rd finger
Wrist
NR
NR
L Ulnar (s)
5th finger
Wrist
NR
2.85
40
2.2
1.88
R Ulnar (s)
5th finger
Wrist
NR
2.70
38
2.0
1.52
L Radial (s)
1th finger
Wrist
2.29
36
5.0
1.36
2.07
44
6.4
1.48
R Radial (s)
1th finger
Wrist
2.37
39
2.4
1.83
2.37
39
2.4
1.83
R Sural (s)
Mild calf
Ankle
3.34
42
3.5
1.83
2.93
48
3.6
1.56
L Sural (s)
Mild calf
Ankle
NR
3.28
43
2.8
1.56
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