polyneuropathy associated with monoclonal IgM

243

J7ournal of Neurology, Neurosurgery, and Psychiatry 1995;59:243-247

Plasma exchange and chlorambucil in polyneuropathy associated with monoclonal IgM gammopathy Eric Oksenhendler, Sylvie Chevret, Jean-Marc Leger, Jean-Pierre Louboutin, Annette Bussel, Jean-Claude Brouet for the IgM-associated Polyneuropathy Study Group (see annex)

Department of Immunology and Hematology E Oksenhendler J-C Brouet Department of Biostatistics S Chevret Department of Hemapheresis, Hopital Saint-Louis, Paris, France A Bussel Department of

Neurology, Hopital Pitie'-Salpeitriere,

Paris, France J-M Leger Department of Neurology, Hopital Laennec, Nantes,

Abstract The study compared chlorambucil alone with chlorambucil in combination with plasma exchange in patients with polyneuropathy associated with monoclonal IgM. Forty four patients were prospectively randomly assigned, in a comparative open trial, to receive either 0.1 mglkg/day chlorambucil orally, for 12 months or chlorambucil associated with 15 courses of plasma exchange, during the first four months of treatment. They were evaluated by a neuropathy disability score and nerve conduction studies. No difference was found between the two treatment groups. The average neuropathy disability score improved by 2-1 points from baseline (21-0 to 18.9) in the chlorambucil group and by 1-8 points (20-4 to 18.6) in the chlorambucil + plasma exchange group (P = 0.70). The mean motor nerve conduction velocity decreased from 20-0 to 18-2 mis in the chlorambucil group and increased from 20 5 to 22-5 mis in the chlorambucil + plasma exchange group (P = 0.51). A slight improvement of the sensory component of the neuropathy disability score (from 10 5 to 8.3) was noted in both groups (P = 0*01). At the end of the study and according to self evaluation, 15 patients-eight from the chlorambucil group and seven from the chlorambucil + plasma exchange group-reported clinical improvement, whereas 15-eight from the chlorambucil group and seven from the chlorambucil + plasma exchange group-reported clinical worsening. Neuropathy remained stable in the others. Thus plasma exchange seemed to confer no additional benefit in the treatment of polyneuropathy associated with monoclonal IgM.

(_

Neurol Neurosurg Psychiatry 1995;59:243-247)

France

J-P Louboutin Correspondence to: Dr Eric Oksenhendler, Service d'Immunopathologie et d'Hematologie, H6pital Saint-Louis, 1 Ave C Vellefaux, 75010 Paris, France. Received 1 1 January 1995 and in final revised form 17 May 1995 Accepted 25 May 1995

Keywords: polyneuropathy; antimyelin; gammopathy; plasma exchange

Peripheral neuropathy may be associated with a serum monoclonal IgM in the presence or absence of an overt lymphoid proliferative disease such as Waldenstrom's macroglobulinaemia.1-3 A causal link between the monoclonal IgM and the development of neuropathy is suggested by (a) the specificity

of most of these IgMs for the myelin associated glycoprotein (MAG),4 5 nerve glycolipids,"8 or gangliosides9; (b) the detection of IgM and complement deposits by immunofluorescence, on the myelin sheaths of nerve biopsies from patients2 10 11; (c) the induction, in animal models, of the neuropathological process through the transfer of the anti-MAG IgM"2 13 or by the subperineural injection of the IgM in peripheral nerves.14 Because IgM associated neuropathy usually has a progressive course and can be responsible for severe disabling sensory and motor symptoms, effective treatment is important. The rationale for using plasma exchange is that the monoclonal IgM may be directly involved in the demyelination and removal of these pathogenic antibodies may prevent progression of the neuropathy or even lead to improvement. The rationale for using chlorambucil is that even in the absence of a detectable lymphoid proliferation, the monoclonal IgM is associated with an underlying IgM producing B cell clone; chlorambucil is effective in chronic B cell neoplasias such as chronic lymphocytic leukaemia and Waldenstr6m's macroglobulinaemia and could therefore be effective on the anti-MAG secreting B cells. Plasma exchange and chlorambucil have been used with some improvement in uncontrolled studies enrolling few patients.' 15-17 As evaluation of these therapeutic strategies require long term treatment and as the idea of a placebo arm was considered unethical because of the progressive disability associated with such disease, we designed a comparative open trial of chlorambucil v chlorambucil associated with plasma exchange. Patients and methods PATIENTS

Patients had to meet the following criteria: (a) polyneuropathy of at least three months duration, (b) presence of a serum monoclonal IgM; (c) a clinical neuropathy disability score (CNDS) above 6 points; (d) a stable or progressive neuropathy; (e) careful elimination of other causes of peripheral neuropathy, especially diabetes and amyloidosis; (D no treatment for the past three months. Informed consent was obtained from each patient. EVALUATION OF NEUROPATHY

The CNDS was determined by modification of the score described elsewhere.'819 Briefly, selected items from the neurological evalua-

244

Oksenhendler, Chevret, Leger, Louboutin, Bussel, Brouet tion were scored and summed. The function of 17 muscles ( x 2) was scored as 0 if normal and 1 if abnormal; sensation (touch-pressure, joint motion, vibration, pin prick) was scored in the same way; muscle stretch reflexes were scored as 0 if present and 1 if absent; pain and paraesthesia were scored 0 if absent and 1 if present. Scores could range from 0 to 72, summing 0 to 46 points for the motor component (CNDS(M)) and 0 to 26 points for the sensory component (CNDS(S)). In addition, after the neurological examination, the patient was asked to assess the evolution of the symptoms as complete remission, improvement, stability, or worsening. Nerve conduction studies were performed on the same lower limb at entry and at the end of the fourth and 12th months. Motor fibres of the peroneal nerve were studied and motor nerve conduction velocities (MNCVs) and distal latencies (DLs) were determined with standard placement of surface electrodes and after control of the limb temperature. Nerve conduction studies were also performed on the sural nerves. Follow up evaluations on individual subjects were performed by a single examiner.

The planned volume of plasma removed by

centrifugation per plasma exchange was 1 5 x total plasma volume. The replacement fluid consisted of a 4% albumin solution (80% of the volume) and macromolecules (20%). Fifteen exchanges were performed during the first four months of treatment: three in the first week, one a week for the next seven weeks, one every 10 days for one

month, and

one

month.

every two weeks for the last

STATISTICAL ANALYSIS Student's t test and x2 test were used for the comparison of the two groups at inclusion.

Changes from baseline were compared in the groups (with and without plasma exchange) by means of the non-parametric two

Wilcoxon rank

sum test. Paired Student's t used to compare results at four and 12 months with baseline data.

test was

Results Inclusion began in December 1986 and ended in August 1990. Forty five patients were enrolled in 15 French centres. Twenty three were assigned to chlorambucil alone and 22 ANTIMYELIN ANTIBODY ACTIVITY to chlorambucil associated with plasma Antimyelin antibody activity was detected by exchange. One patient from the chlorambucil an indirect immunofluorescence assay on group had severe chronic hepatopathy, and human sciatic nerve and confirmed with therefore the data for this patient were not immunoblotting experiments. used in the analysis. The mean (SD) Karnofsky score for the STUDY DESIGN whole population was 73 (12)%. Walking was The study was designed to be a prospective, difficult or unstable in twenty eight (64%) randomised, open clinical trial comparing two patients. Two patients had been treatments. Before the study was designed, lit- treated with immunosuppressive previously agents, one tle reliable information on the natural history with cyclophosphamide and one with azathioof IgM associated neuropathy was available, prine. The mean duration of the peri(SD) and spontaneous improvement had not been pheral neuropathy was 37 (35) months. reported. Using a unilateral formulation and Nerve/muscle were performed in 32 biopsies expecting an improvement of at least 10 patients before On semi-thin sections points of the initial CNDS in the group the myelinated entry. nerve fibre population was treated with chlorambucil and plasma reduced; teased fibre studies showed a mixexchange and postulating that the disease ture of segmental demyelination and remyeliwould be stable in the group receiving nation in most cases; muscle atrophy was chlorambucil alone, we decided to enroll 44 present in 26 cases (81 %). The randomisation consecutive patients in the study (a = 0 05, procedure resulted in treatment groups that ,B = 0-05). were well balanced with respect to patient characteristics (table 1) and neurological TREATMENT abnormalities (tables 2 and 3). The patients were assigned by randomisation None of the patients stopped treatment to receive chlorambucil alone (O- 1 mg/kg/day, because of toxicity; 10 patients orally) for 12 months, or in association with a experienced temporaryhowever, of chlosuspension four month period of plasma exchange. rambucil or required tapering of the dosage Table 1 Patient characteristics at study entry according to treatment group Chlorambucil No of patients M/F

Age (mean (SD)) Bone marrow lymphoplasmocytic infiltration Serum IgM (mean (SD)) (g/l)

Kappa/lambda* Cryoglobulinaemia Antimyelin IgMt

22

19/3 64 (9-5) 5

5-6 (4-4) 16/7 3 17/21

Neuropathic indices at study entry according to Chlorambucil

22 18/4 64 (9 3) 6

Chlorambucil No of patients Duration of neuropathy

(months) CNDS CNDS(M) CNDS(S)

5-2 (4) 19/6 0 16/21

*Biclonality in four patients; tindirect immunofluorescence assay (done on 21 patients

group).

Table 2

treatment group

Chlorambucil and plasma exchange

in each

Values

and plasma exchange

22

22

36 (33) 21 (9 0) 9-6 (5-7) 11-3 (5 0)

38 (37) 20-4 (6 5) 11-2 (4 8) 9-2 (4-0)

are means (SD). CNDS = clinical disability score; CNDS(M) = motor componentneuropathy of the CNDS; CNDS(S) = sensory component of the CNDS.

245

Plasma exchange and chlorambucil in polyneuropathy associated with monoclonal IgM gammopathy

cant (P < 0-01). By contrast, the motor component of the CNDS increased (worsened) by 04 points in the chlorambucil group and Chlorambucil and (improved) by 0 3 points in the decreased plasma exchange Chlorambucil chlorambucil + plasma exchange group. (n = 19) (n = 20) Neither difference was significant. (P = 070 Peroneal nerve: and P = 0a 12 respectively; tables 4 and 5). 15 15 Detectable response 26-7 (11-3) MNCV (mean (SD)) 26-2 (10-9) According to self evaluation after 12 12 4 (6 2) 11-3 (6-5) DL (mean (SD)) of treatment, the neurological sympmonths 4 5 response Undetectable Sural nerve: resolved in one patient under completely toms 4 3 Detectable response improved in 14 patients and chlorambucil 15 Undetectable response 17 the neuropathy was in each group); (seven MNCV = motor nerve conduction velocity (m/s), DL = distal stable in 14 patients (six in the chlorambucil latency (ms). group and eight in the chlorambucil + plasma exchange group); it had worsened in 15 during the trial because of haematotoxicity. patients (eight in the chlorambucil group and No serious adverse events were reported with seven in the chlorambucil + plasma exchange plasma exchange. Eight patients stopped the group). There was no difference between the treatment before month 12. In the chloram- two groups as a result of treatment. Electrophysiological data were available in bucil group, four patients stopped treatment (three because of neurological progression 39 patients. Nerve conduction studies showed (months 2, 7, and 9) and one because of the that with chlorambucil alone, the mean value absence of improvement (month 4)). Three of of MNCV (peroneal nerve) worsened by 1-8 them were then treated with plasma exchange m/s and that the mean value of DL improved but remained in the chlorambucil alone group by 3-3 ms. In the chlorambucil + plasma for an intent to treat analysis. In the chloram- exchange group the mean value of MNCV bucil + plasma exchange group, one patient improved by 2 m/s and the mean value of DL died at month 4 with an occlusion of the small by 3 ms. The differences between the two bowel and three stopped treatment, two groups were not significant. Sensory nerve because of worsening of neuropathy at conduction velocities in the sural nerve were months 4 and 6, and one because of emer- undetectable in 32 of the 39 patients at entry, and in 21 of the 32 patients evaluated at gency vascular surgery at month 4. 12. month been The major endpoint of the study had Twenty nine patients remained stable or defined as the CNDS after 12 months of treatment. On average, the CNDS decreased worsened, and 15 improved after treatment. (improved) by 2 1 points in the chlorambucil We looked for baseline covariates that could group and by 1 8 points in the chlorambucil + be predictive for the response, and failed to plasma exchange group. The difference find any predictive value for age, sex, bone between the two groups was not statistically marrow lymphoid infiltration, serum IgM significant (P = 070). The slight improve- concentration, antimyelin activity, or initial ment in both groups was related to an CNDS; There was a trend for shorter duraimprovement of the sensory component of the tion of the neuropathy in the responders (26-3 CNDS: 2-4 points in the chlorambucil group (23) months) than in the non-responders and 1-5 points in the chlorambucil + plasma (42.6 (40) months), but it did not reach sigexchange group. In the whole population of nificance (P = 0-15). The response was not patients this improvement of the CNDS(S) associated with a significant decrease in the score from 10-5 to 8-3 was statistically signifi- serum IgM concentration in the 29 patients in whom it could be evaluated. Long term follow up (47 to 83 months) was available for 14 of the 15 patients who had Table 4 Evolution from baseline in neuropathic indices during the 12 month treatment responded to treatment. At the end of the period, according to treatment group study two of them stopped taking chlorambuChlorambucil and one patient had achieved a complete cil; plasma exchange P value Chlorambucil response and remained symptom free after 80 CNDS: months while the serum monoclonal IgM was 20 4 (6 5) 21-0 (9-0) At entry 0-74 still detectable (2 to 3 g/l); the other relapsed at 21 1 (8 3) 20-6 (7 8) Month 4 0 70 18-6 (7 6) 18-9 (8 2) Month 12 24 but improved again when chlorammonth CNDS(M): bucil was reintroduced. Of the 12 patients 11-2 (4-8) 9-6 (5 7) At entry 0-21 11-6(48) 10-4(48) Month4 who were maintained on chlorambucil, six 0 12 10 9 (4 7) 10 0 (4 3) Month 12 remained stable on treatment, four stopped CNDS(S): Table 3 Nerve conduction study at entry according to treatment group

At entry Month4 Month 12

MNCV: All patients: At entry Month 4 Month 12 Patients with detectable response at baseline: At entry Month 4 Month 12

11-3 (5 0) 10-3 (4-8) 8-9 (5 4)

9-2 (4-0) 9 5 (5 4) 7-7 (4 3)

20-0 (14-8) 20 6 (13-0) 18-2 (10 1)

20-5 (15 3) 22-0 (18-0) 22-5 (14-7)

26-2 (10 9) 25-7 (12-0) 24-3 (12-4)

26-7 (11-3) 27-9 (15-4) 274 (13-8)

0 57 0 70

Table 5 Evolution from baseline in neuropathic indices during the 12 month treatment period 0-79 0-51 0-72 040

Values are means (SD). CDNS = clinical neuropathy ((M) = motor component; (S) = sensory component); MNCV = motor nerve conduction velocity.

At entry

CNDS CNDS(M) CNDS(S)

MNCV

21-0 10-5 10-5 20 2

(7 8) (5-3) (4 5) (14 8)

For explanations see table 4.

Month 12

P value

18 8 (7 8) 10-5 (4 4) 8.3 (4 9) 19 9 (12-0)

0.01

0 05 0 97

0-51

Oksenhendler, Chevret, Leger, Louboutin, Bussel, Brouet

246

chlorambucil after 19 to 36 months and remained stable, and two worsened on treatment.

Discussion

Peripheral neuropathy associated with monoclonal IgM gammopathy is usually considered as a specific entity.2021 The clinical features are somewhat different from those with IgG or IgA gammopathies, with more sensory loss and ataxia. A causal link between the monoclonal IgM and the development of neuropathy is suggested by the antibody activity of the IgM to nerve polypeptides or glycolipids, the detection of IgM deposits on the myelin sheaths of patients' nerve biopsies, and the induction of the neuropathological process through the transfer of the anti-MAG IgM in animal models. These data provided a firm basis to evaluate plasma exchange as well as chlorambucil in such patients with the aim of obtaining a significant reduction of IgM production or circulation. Previous reports that plasma exchange might be efficient in polyneuropathy associated with IgM monoclonal gammopathy of undetermined significance needed to be confirmed, as most trials were uncontrolled and performed in selected patients, without prospective evaluation of the neurological symptoms. In the present study, the association of plasma exchange with chlorambucil offered no additional benefit as measured by the neuropathy disability score (P = 070), its motor component (P = 0-12), its sensory component (P = 070), or the motor nerve conduction velocity (P = 0-5 1). Interestingly, after four months of treatment, when the patients of one group had completed their plasma exchange that is, at the time at which we were most likely to detect a difference between the two groups-we failed to show any usefulness of plasma exchange (table 4). For both groups together, treatment was associated with a slight improvement of the CNDS, from 21-0 to 18-8 (P = 005) as a sole result of the improvement its sensory component, from 10-5 to 8-3 (P = 0 01). There was no significant modification of the nerve conduction velocity neither of the distal latency. Of note, after 12 months of treatment, there was no obvious modification of the serum IgM concentration in patients reporting

improvement.

These results are consistent with those of

Dyck et al in their double blind trial in which plasma exchange might be effective in improving the neuropathy disability score in patients with neuropathy associated with monoclonal IgG or IgA gammopathies but not in the patients with monoclonal JgM.22 The conditions in our study were, however,

different: (a) the study was open, without a placebo arm, (b) the plasma exchange programme was longer (15 courses over four months v six courses over three weeks), (c) the effectiveness of treatment was evaluated at month 12 instead of week 3. When short term

effectiveness was evaluated at month 4, however, we still did not detect any differences between the groups. Our data suggest that in polyneuropathy associated with monoclonal IgM gammopathy, plasma exchange does not offer benefit over chlorambucil alone. Previous data pointing to an improvement of the neuropathy with plasma exchange indicate that such treatment could be effective in a limited subset of patients not detected in the present study. Chlorambucil may improve the symptoms in some patients and therefore can be considered as a possible treatment in severely disabled patients. Because of the possible risk of secondary leukaemia during long term chlorambucil treatment, future prospective randomised trials should evaluate the effects of other types of immune modulation such as intravenous high dose polyvalent immunoglobulin-2325 or a-interferon, which may act either through interference with the antibody activity of the IgM or with the underlying B cell clonal disorder. Annex: the IgM associated polyneuropathy study group Francis Bauters, Service d'Hematologie, H6pital C. Huriez, Lilles; Pierre Bouche, Clinique des Maladies du Systeme Nerveux, H6pital de la Salpetriere, Paris; Jean-Claude Brouet, Service d'Immuno-Hematologie, H6pital Saint-Louis, Paris; Annette Bussel, Unite d'Hemapherese, H6pital Saint-Louis, Paris; Francois Chedru, Service de Medecine Inteme et Neurologie, Centre Hospitalier de Meaux; Sylvie Chevret et Claude Chastang, Department de Biostatistiques Medicales, de H6pital Saint-Louis, Paris; Francois Chollet, ServicePierre Neurologie, Centre Hospitalier Purpan, Toulouse; Clavelou, Service de Neurologie, Centre hospitalier de Clermond-Ferrand; Bertrand Couret, Service de Medecine Inteme, Centre Hospitalier Purpan, Toulouse; Francoise Danon, Laboratoire d'Immunologie, H6pital Saint-Louis, Paris; Isabelle Desbois, Service d'Oncologie et d'Hematologie, H6pital Bretonneau, Tours; Marine Divine, Service d'Hematologie, H6pital Henri-Mondor, Creteil; Frederic Dubas, Service de Neurologie, Centre hospitalier d'Angers; Jean-Paul Fermand, Service d'Immuno-Hematologie, Hospital Saint-Louis, Paris; Bernard Grosbois, Service de Rennes; Jean-Luc d'Hematologie, Centre hospitalier Centre hospitalier HotelHarousseau, Service d'Hematologie, Dieu, Nantes; Jean-Michel James, Consultation d'Hematologie, H6pital Saint-Joseph, Paris; Jean-Marc Leger, Clinique des Maladies du Systeme Nerveux, H6pital de la Salpetriere, Paris; Jean-Pierre Louboutin, Service de Neurologie, H6pital Laennec, Nantes; Stephane Metral, Explorations Fonctionnelles Neurologiques, H6pital du Kremlin-Bicetre; Jean-Philippe Neau, Service de Neurologie, Centre hospitalier de Poitiers; Eric Oksenhendler, Service Paris; Michel d'Immuno-Hematologie, H6pital Saint-Louis, Ruel, Service de Medecine Interne, Centre Hospitalier de de Service Annette Schaeffer, Senlis; Medecine Inteme, Creteil; Didier Vincent, Service de H6pital Henri-Mondor, Neurologie, H6pital de Saintes, Paris. 1 Dalakas MC, Engel WK. Polyneuropathy with monoclonal gammopathy: studies of 11 patients. Ann Neurol 198 1*10:45-52. 2 Smith IS, Kahn SN, Lacey BW, et al. Chronic demyelinating neuropathy associated with benign IgM paraproteinemia. Brain 1983;106:169-95. 3 Dellagi K, Dupouey P, Brouet JC, et al. Waldenstrom's a clinical macroglobulinemia and peripheral neuropathy: and immunologic study of 25 patients. Blood 1983;62: 280-5. 4 Latov N, Sherman WH, Nemni R, et al. Plasma-cell dyscrasia and peripheral neuropathy Nwith a monoclonal antibody to peripheral-nerve myelin. Engl3 Med 1980; 303:618-21. 5 Braun PE, Frail DE, Latov N. Myelin-associated glycoprotein is theJ antigen for a monoclonal IgM in polyneuropathy. Neurochem 1982;39:1261-5. 6 Chou DKH, Ilyas AA, Evans JE, et al. Structure of a with monoclonal IgM in neuropathy glycolipid reacting Biochem and with HNK1. Biophys Res Commun 1985; 128:283. 7 Hauttecceur B, Schmitt C, Dubois C, et al. Reactivity of human monoclonal IgM with nerve glycosphingolipids. Clin Exp Immunol 1990;80:181. 8 Jauberteau MO, Henin D, Bouche P, et al. Etude des anticorps anti-glycolipides au cours des dysglobulinemies

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