Effect of stem cell transplantation for B-cell malignancies on disease course of associated polyneuropathy

A. C. J. Stork 0 1 2 W. L. van der Pol 0 1 2 D. van Kessel 0 1 2 H. M. Lokhorst 0 1 2 N. C. Notermans 0 1 2 0 H. M. Lokhorst Department of Hematology, University Medical Center , Utrecht, The Netherlands 1 A. C. J. Stork (&) Department of Neuromuscular Diseases, Rudolf Magnus Institute of Neuroscience , P.O. Box 85500, 3508 GA Utrecht, The Netherlands 2 A. C. J. Stork W. L. van der Pol D. van Kessel N. C. Notermans Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center , Utrecht, The Netherlands B cell dyscrasias are often refractory to medical treatments, and hematological stem cell therapy (SCT) may be warranted. It is not clear whether an associated polyneuropathy may also profit from SCT. In exceptional cases SCT has been tried in patients with monoclonal gammopathy and progressive polyneuropathy refractory to medical treatments. In a cohort of 225 patients with monoclonal gammopathy and polyneuropathy, we selected the six patients who underwent SCT and retrospectively examined the effects of SCT on the disease course of the associated polyneuropathy. In all patients except one, the indication for SCT was hemato-oncological (multiple myeloma in 4 patients and primary AL amyloidosis in 1). The remaining patient had an IgG monoclonal gammopathy of undetermined significance and a progressive and painful polyneuropathy for which she was treated with SCT. SCT led to improvement of motor scores and autonomic symptoms in one patient; three patients experienced improvement of neuropathic pain or sensory deficits but showed further progression of weakness. One patient showed no improvement at all. One patient died within 100 days after - SCT. In conclusion, SCT as a treatment of refractory hematological malignancy may occasionally have a positive effect on the associated progressive polyneuropathy, although the benefits are very limited and the treatmentrelated mortality is high. B cell dyscrasias are associated with polyneuropathies. A variety of pathogenetic mechanisms, including cytokinemediated damage, nerve infiltration, synthesis and deposition of noxious monoclonal proteins or binding of monoclonal antibodies to nerve constituents, may cause neuropathy in patients with B cell disorders. The disease course of these polyneuropathies may be mild, but can also be very debilitating, causing severe sensorimotor deficits and autonomic dysfunction [1, 2]. Unfortunately, polyneuropathy associated with monoclonal gammopathy is often refractory to treatment. Intravenous immunoglobulins (IVIg) and the anti-CD20 monoclonal antibody rituximab may ameliorate the disease course in a minority of patients [3, 4]. Hematological stem cell therapy (SCT) is a well-established therapy used for refractory hematological malignancies. SCT has been reported to attenuate the progressive disease course of patients with polyneuropathy with organomegaly, endocrinopathy, M-protein and skin changes (POEMS) [5, 6], chronic inflammatory demyelinating polyneuropathy (CIDP) [7, 8], primary AL amyloidosis [9], and recently in a small series of patients with IgG MGUS- or MM-associated neuropathy [10], but it is unknown whether SCT may represent a rescue therapy for a wider range of patients with polyneuropathy and B cell dyscrasias and whether the possible beneficial effects outweigh risks associated with SCT. Here we describe six patients with malignancy-associated polyneuropathy receiving SCT primarily for the treatment of their hematological disorders and report on the effects on the neuropathy. Patients and methods Patient characteristics Six patients (2.7%) from a cohort of 225 patients [11] with polyneuropathy and B cell dyscrasia underwent SCT. The primary indication for SCT was the hematological malignancy in all patients with the exception of patient 5, in whom improvement of the polyneuropathy was the main goal. Clinical data and data from nerve conduction studies were collected prospectively following a standardized protocol that has been in use for this patient group since 1985. These data were analyzed retrospectively to asses the effect of SCT on the course of the polyneuropathy. Patient characteristics are summarized in Table 1. All patients presented with complaints consistent with polyneuropathy, with B cell dyscrasia found during the neuropathy work-up. Four patients had multiple myeloma (MM) unresponsive to other treatments (patients 1, 2, 3 and 6), one had light chain (AL) amyloidosis, and one patient had an IgG MGUS and a rapidly progressive demyelinating polyneuropathy despite treatment with IVIg and glucocorticosteroids (patient 5). With the exception of patient 1, who had a monozygous twin brother who acted as a donor, all patients were treated with autologous SCT. All transplantations were carried out in the Utrecht Medical Center, a tertiary referral center for hemato-oncology and (autologous) stem cell transplantation. Institutional morbidity and mortality lie well within international standards, as published elsewhere (10% treatment related mortality in MM patients) [11]. Neurological examinations before and 1 year after stem cell transplantation were performed using a standardized protocol, described elsewhere [12]. Motor function was expressed using the Modified Medical Research Council (MRC) motor sum score of 14 muscle groups in both arms and legs, with a maximum score of 140 points. Sensory function was expressed as a sensory composite sum score consisting of scores for sense of touch (04), pain (04) and vibration (04) in both arms and legs, and position sense (02) in both legs with a maximum of 56 points [12]. The modified Rankin score, (ranging from 0 for no symptoms at all to 5 for severely disabled and bedridden and 6 for dead) was used to quantify functional disability. All patients underwent systematic nerve conduction studies using a previously described protocol [12]. Demyelination was defined according to previously established criteria. Nerve conduction studies that showed a reduction of CMAP amplitudes to less than 20% of normal values in at least two nerves but did not meet the criteria for demyelination were scored as axonal [13]. Other causes of polyneuropathy than monoclonal gammopathy were excluded following a standardized protocol [12]. Table 1 Patients age at first visit in our neuromuscular clinic, paraprotein, hematological diagnosis and predominant clinical manifestation of the polyneuropathy Patient Age Paraprotein Hematological Polyneuropathy diagnosis Clinical effect of SCT on polyneuropathy Before After Before After Before After Motor sum score, sensory sum score, modified ranking score, before and after treatment. Overall clinical result. (*) died before 1 year follow-up Case histories and results (Table 1) Patient 1 was diagnosed with MM with IgA monoclonal gammopathy and had a progressive, predominantly motor neuropathy, with severe weakness, hypesthesia and paresthesia in the lower legs and h (...truncated)