Abstract
Background: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare multisystem disorder associated with plasma cell dyscrasia. There is increasing evidence that high-dose chemotherapy with autologous peripheral blood stem cell transplantation (Auto-PBSCT) is an efficacious treatment.
Objective: To elucidate the extent and time course of neurologic improvement after Auto-PBSCT in patients with POEMS syndrome.
Methods: Clinical and electrophysiologic findings in nine patients were reviewed. The median follow-up period was 20 months (range, 8 to 49 months). Serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA.
Results: Serum VEGF levels rapidly decreased a month after Auto-PBSCT. Within 3 months, neurologic improvement began, and all the patients showed substantial neurologic recovery during the next 3 months. Particularly, three initially chairbound patients regained ability to walk at 6 months. Nerve conduction studies showed significant increases in conduction velocities and amplitudes within 6 months of treatment. At the end of follow-up periods, neuropathy was still improving, and no patients had recurrence of symptoms.
Conclusion: Autologous peripheral blood stem cell transplantation results in obvious neurologic improvement within 6 months, presumably by extensive axonal regeneration and remyelination. This therapy could be considered as a first line treatment for patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome with younger onset even if they are tetraplegic.
Glossary
- Auto-PBSCT=
- autologous peripheral blood stem cell transplantation;
- CMAP=
- compound muscle action potentials;
- MCV=
- motor conduction velocities;
- POEMS=
- polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes;
- VEGF=
- vascular endothelial growth factor.
Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating-axonal mixed neuropathy with multiorgan involvement and plasma cell dyscrasia.1–4 The pathogenesis of POEMS syndrome is not fully elucidated. Particularly, mechanisms of peripheral neuropathy are unknown, but overproduction of vascular endothelial growth factor (VEGF), presumably secreted by plasmacytoma, is considered responsible for the characteristic symptoms such as angiomata, edema/effusion, and organomegaly.5,6 POEMS syndrome is a potentially fatal disorder, and patients' quality of life frequently deteriorates because of progressive neuropathy.1,2
Since around 2000, several case reports and case series have shown beneficial effects of high-dose chemotherapy with autologous peripheral blood stem cell transplantation (Auto-PBSCT).7–10 Most of the reports described improvement in neuropathy, as well as non-neurologic symptoms, but the detailed extent and time course of neurologic recovery have not systematically been evaluated. We therefore reviewed neurologic improvement in nine patients with POEMS syndrome who were treated with Auto-PBSCT, with serial results of neurologic disability scaling, nerve conduction studies, and serum VEGF levels.
METHODS
Patients.
Between 2003 and 2006, 20 patients with POEMS syndrome were seen at Chiba University Hospital. Of these, nine patients (seven men and two women) fulfilled our criteria for treatment with high-dose chemotherapy with Auto-PBSCT (table). Inclusion criteria were age at entry <66 years, no serious organ involvement such as renal, respiratory, and heart failure, and no active infection. Patients with severe tetraplegia due to peripheral neuropathy were not excluded because neuropathy was primarily caused by the disorder, and therefore Auto-PBSCT was expected to improve neuropathy. Their mean age was 49 years (range, 38 to 55 years). Clinical and laboratory data of four patients (nos. 1–4) were described in our previous report.10 Almost all the patients had the five features of POEMS, as well as multiple osteosclerotic lesions, pleural effusion/ascites/peripheral edema, and increased serum VEGF levels, and were diagnosed with definite POEMS syndrome according to the published criteria.11 All nine had motor-sensory polyneuropathy, predominantly affecting the lower limbs. At entry, five of the patients were unable to walk independently due to severe motor weakness, and three (nos. 7–9) were chair- or bedbound. Vibratory, tactile, and pain sensations decreased predominantly in the distal limbs in all. Autonomic symptoms were not main features, but three noticed decreased sweating in their lower body. None had urinary disturbance.
Table Patient findings before and after transplantation
Treatment regimen.
Autologous peripheral blood stem cell collection was performed after mobilization by chemotherapy (IV cyclophosphamide, 2 g/m2/day for 2 consecutive days) with subcutaneous granulocyte colony-stimulating factor. High-dose melphalan chemotherapy (100 mg/m2/day for 2 consecutive days) and Auto-PBSCT was performed approximately 1 month after blood stem cell collection according to the standard regimen of treatment for multiple myeloma. All patients gave written informed consent to the treatment protocol which was approved by an Institutional Review Board of Chiba University Hospital.
Assessments.
Clinical and laboratory assessments were prospectively performed. Neurologic examination was performed every month, and patients' disability was evaluated with Hughes functional grading scale: 0, normal; 1, able to run; 2, able to walk 5 m independently; 3, able to walk 5 m with aids; 4, unable to stand (chair- or bedbound). CT of the chest and abdomen was performed every 3 months to examine pericardial/pleural effusion and ascites. Serum VEGF levels were measured by ELISA every 3 months as described elsewhere,10 and nerve conduction studies were performed every 3 months. For nerve conduction indices, we analyzed only median and ulnar motor nerve conduction velocities and amplitudes of compound muscle action potentials, because motor responses in lower limb nerve studies and sensory nerve action potentials were frequently absent in patients with POEMS syndrome.
For statistics, median regression analyses were performed using QUANTREG procedure of SAS version 9.3.1 software (SAS Institute Japan, Tokyo, Japan). Common regression lines were estimated for analyses of clinical (grip strength) and nerve conduction indices (nerve conduction velocities and amplitudes of compound muscle action potential).
RESULTS
No toxic death or serious adverse effects occurred during stem cell mobilization and Auto-PBSCT. Neutrophil and platelet recoveries occurred within 15 days. A month after the Auto-PBSCT treatment, there was a marked decrease in serum VEGF levels (figure 1A), whereas the decrease was not sufficient in one patient (no. 5). At the end of follow-up, serum VEGF levels were within normal limit in seven of the patients (table). Capillary leak symptoms such as peripheral edema, pleural effusion, and ascites completely disappeared 3 months after Auto-PBSCT.
Figure 1 Serial changes in serum levels of vascular endothelial growth factor (VEGF; A) and grip strength of the right hand (B) after autologous peripheral blood stem cell transplantation
Note rapid decreases in VEGF levels, and subsequent increases in grip power. A dotted line in A indicates the upper normal limit. In B, a bold line indicates common median regression line (Y = 0.86X + 12.29; p < 0.0001).
Neurologic improvement began 1 to 3 months after treatment, and all the nine patients showed substantial neurologic recovery. The table shows sequential data of Hughes grade; at 6 months seven had improvement in the scale by 1 or more grade, and at the end of follow-up, six were able to run. Patients 7–9 had severe disability and were chair- or bedbound before treatment; lower limb muscle strength was graded as 0/5–1/5 in the distal muscles, and as 1/5–2/5 in the proximal muscles on the MRC scale. Patients 7 and 8 regained to ability to walk independently at 12 months, and Patient 9 was able to walk with a stick at 8 months. Six patients (nos. 1–6) returned to work or nearly normal daily activities. Sensory disturbances were lessened in all nine patients, although quantitative measurements were not performed.
Figure 1B shows sequential changes in grip strength of the right hand. There was a substantial improvement through 12 months after Auto-PBSCT. Serial findings of median motor nerve conduction studies are shown in figure 2. There was a gradual but obvious improvement in nerve conduction velocities up to 20 months; in two patients (nos. 2 and 4) nerve conduction velocities were normal 12 months after treatment. Amplitudes of compound muscle action potentials tended to be greater in nearly all the patients. At the end of the follow-up periods, none of the nine patients showed recurrence of the neuropathic and non-neurologic symptoms.
Figure 2 Sequential findings of median nerve motor conduction velocities (MCV) and amplitude of compound muscle action potentials (CMAP)
Note substantial increases in MCV and CMAP amplitude during 12 months after treatment with autologous peripheral blood stem cell transplantation. Bold lines indicate common median regression lines (A; Y = 0.39X + 35.03; p = 0.0084; B; Y = 0.23X + 4.65; p = 0.0002).
DISCUSSION
Our results show that high-dose melphalan chemotherapy with Auto-PBSCT is a markedly effective treatment for POEMS syndrome. Although this is an open trial including a small number of patients, neurologic recovery was substantial in all the patients who received Auto-PBSCT treatment, leading to an improvement in patients' quality of life. Particularly, three of the nine who were chair- or bedbound before treatment regained ability to walk 6 months after Auto-PBSCT. We suggest that neurologic recovery is substantial after Auto-PBSCT, and therefore this treatment could be considered as a first-line therapy for POEMS syndrome.
A number of reports demonstrated that Auto-PBSCT results in clinical remission,7–9 but the extent and time course of neurologic improvement have rarely been described, presumably because previous reports were published in hematology journals. This study demonstrated detailed neurologic examination, nerve conduction study results, and serum VEGF levels, all of which support benefits of Auto-PBSCT. So far, previous studies have reported over 40 patients who were treated with Auto-PBSCT, and there were two transplant-related deaths.9 The frequency of transplant-related death is therefore estimated as approximately 5% at present, and this is a major problem of this treatment. Our previous study showed outcome of eight patients treated with conventional melphalan chemotherapy for 2 years10,12; four of them actually respond to the chemotherapy, but an improvement in neuropathic symptoms were very slow and incomplete, being gradually lessened over 12 to 24 months. Three of the eight died 5 to 9 years after the initiation of chemotherapy.
Our findings of nerve conduction studies suggest that extensive axonal regeneration and remyelination can develop after Auto-PBSCT. Neuropathologic studies in POEMS syndrome have shown a mixture of demyelination and axonal degeneration.13,14 Uncompacted myelin lamellae are found in most cases, and have been suggested to be highly characteristic for this syndrome. Segmental demyelination, particularly in the proximal nerve segments, and axonal degeneration in the distal nerve segments are also frequently seen.13,14 These pathologic changes are potentially mediated not only by VEGF, but also by other cytokines or inflammatory substances. We speculate that high-dose chemotherapy with Auto-PBSCT can normalize multiple changes in the cytokine network by decreasing dyscrasic plasma cells. Under such conditions, prominent axonal regeneration, as well as remyelination, may occur.
Further studies are required to examine long-term outcomes in patients who received high-dose melphalan chemotherapy with Auto-PBSCT, and one of our patients actually showed incomplete reduction in serum VEGF levels (figure 1A), suggesting reproliferation of monoclonal plasma cells. Moreover, Auto-PBSCT is possibly associated with serious adverse effects including transplant-related death, and indication of this treatment should be carefully determined. Nevertheless, based on dramatic improvement in neuropathy shown in our patients, we suggest that high-dose chemotherapy with Auto-PBSCT could be considered as a first-line treatment for appropriate candidates. In this series, only 9 of the 20 patients underwent Auto-PBSCT, and the remaining 11 could not receive this treatment because of high age (>65 years), renal failure, or active infection. For such patients, anti-VEGF monoclonal antibody (bevacizumab),15 thalidomide,16,17 or lenalidomide18 could be a new treatment option.
Footnotes
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Editorial, page 1658
e-Pub ahead of print on October 1, 2008, at www.neurology.org.
Supported in part by a grant for research on intractable diseases from the Ministry of Health, Labour and Welfare of Japan (S.K.).
Disclosure: The authors report no disclosures.
Received January 10, 2008. Accepted in final form May 5, 2008.
REFERENCES
Letters: Rapid online correspondence
- Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome
- Reply from the authors
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