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Related Collections Transplantation Brief Reports Clinical Trials and Observations Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 April 2002, Vol. 99, No. 8, pp. 3057-3059 BRIEF REPORT High-dose therapy and autologous blood stem cell transplantation in POEMS syndrome Arnaud Jaccard, Bruno Royer, Dominique Bordessoule, Jean-Claude Brouet, and Jean-Paul Fermand From the Hematology Unit, Centre Hospitalier Universitaire, Limoges, France, and Immuno-Hematology Unit, Hôpital Saint-Louis, Paris, France.     Abstract Top Abstract Introduction Study design Results and discussion References We treated 5 patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome and multifocal bone lesions or diffuse bone marrow plasmacytic infiltration with high-dose therapy (HDT) and autologous blood stem cell transplantation. In all cases, the treatment produced remission of plasma cell proliferation associated with marked improvement in the patients' performance status, neurologic symptoms, and other manifestations of the syndrome. HDT with stem cell support should be investigated further as a therapeutic option in patients with POEMS syndrome and disseminated plasma cell dyscrasia. (Blood. 2002;99:3057-3059) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a multisystem disorder initially described by Japanese authors1 and then reported in Europe and North America.2-4 It is characterized by the combination of conditions that make up its abbreviation and may also include systemic symptoms, edema and anasarca, thrombocytosis, and various other manifestations.1-4 This syndrome is associated with a plasma cell dyscrasia having some unique features such as osteosclerotic bone lesions and -light chain isotype of secreted monoclonal immunoglobulin (MIg).1-4 The pathogenesis of POEMS syndrome is still unknown, but all symptoms are likely secondary to the plasma cell proliferation as supported by the dramatic improvement that may be obtained by radiotherapy and/or surgical excision in patients with solitary plasmocytoma and by the reappearance of POEMS symptoms when bone lesions recur.5,6 In patients with diffuse bone marrow infiltration or multifocal lesions, conventional chemotherapy is usually proposed, but patient's quality of life most often deteriorates because of progressive neuropathy.7,8 Because of the well-established dose-response effect of melphalan in myeloma patients,9 we explored high-dose therapy (HDT) and stem cell rescue as an alternative approach in 5 patients.     Study design Top Abstract Introduction Study design Results and discussion References Diagnosis of POEMS syndrome was considered in patients who presented with plasma cell proliferation associated with peripheral neuropathy, in the absence of any known cause of nerve involvement. All patients with multifocal bone lesions or diffuse bone marrow plasmatic infiltration were offered the option of HDT followed by autologous transplantation. Since 1996, 5 patients (of 9 patients with POEMS) fulfilled these criteria. All gave informed consent and received HDT. They were between 44 and 62 years of age. Table 1 lists the main elements of POEMS in each patient. Monoclonal IgA and IgG were detected in the serum of 3 and 1 patients, respectively. The last patient had a biclonal IgM and IgG gammopathy. In all cases, the monoclonal component was small, below 10 g/L, and polyclonal immunoglobulin level was normal. One patient (case 3) had nephrotic syndrome, and renal biopsy showed glomerular alterations, including cellular proliferation and mesangiolysis that suggested POEMS nephropathy10,11; congo red staining was negative.                                View this table: [in this window] [in a new window]   Table 1. Main characteristics of patients with POEMS syndrome Three patients had multiple bone lesions that were purely osteosclerotic and mixed, osteosclerotic and osteolytic, in 1 and 2 cases, respectively. In these patients, standard bone marrow examinations were normal, and the plasmacytic nature of the bone lesions was proven by a focal biopsy. One patient (case 5) presented with solitary mixed iliac plasmocytoma and has diffuse bone marrow infiltration by monotypic plasma cells bearing  light chains. Patient 3 had no detectable bone lesion but diffuse bone marrow lymphoplasmacytic infiltration. Appropriate staining of biopsies did not detect AL amyloidosis in any case. All patients had distal bilateral sensory disturbance predominating in the lower limbs, associated with abolition of deep tendon reflexes. Two patients also presented with motor deficiency, including one who was bedridden because of tetraparesia. Isolated increase in protein level (above 1 g/L) was detected in the cerebrospinal fluid of the 4 studied patients. Electromyographic studies provided evidence for demyelinating lesions in all patients either isolated (n = 2) or associated with axonal degeneration (n = 3). Other manifestations of POEMS syndrome (Table 1) included organomegaly in 3 patients; impotence, diabetes mellitus, adrenal insufficiency, and/or hypothyroidism in 4 patients; skin changes in 4 patients (hyperpigmentation in 3, telangiectasia in 1); and peripheral edema in 3 patients, associated with papilledema in 2 cases. In all cases, blood cell counts were normal. As indicated in Table 2, patient 1 was initially considered to have Guillain-Barré syndrome and progressively became bedridden despite various therapeutic attempts. Other patients had been briefly or not previously treated.                                View this table: [in this window] [in a new window]   Table 2. Therapy and patients' outcome Patients were treated as follows: (1) Local radiation was considered in the patients who had a prominent focal bone lesion and was actually performed in 3 patients. (2) Autologous peripheral blood stem cell (PBSC) collection was performed after mobilization by chemotherapy (intravenous cyclophosphamide over 2 days, 60 mg/kg/d) plus subcutaneous granulocyte colony-stimulating factor (G-CSF, 5 µg/kg/d). (3) HDT and PBSC transplantations were performed about 1 month after PBSC collection according to the regimens listed in Table 2.     Results and discussion Top Abstract Introduction Study design Results and discussion References All 5 patients in whom we planned to perform HDT actually received this treatment. No toxic deaths occurred during PBSC mobilization or transplantation. Posttransplant neutrophil and platelet recoveries (> 500 × 106/L and > 50 × 109/L, respectively) occurred within 15 days and were sustained in all cases. The morbidity of the procedure, including mucositis and culture-negative neutropenic fever for 2 to 6 days, was not unexpected in any case, including in the patient who received sequential HDT and tandem transplantation while bedridden. Thus, in contrast to AL amyloidosis,12,13 the unique features of POEMS syndrome, particularly osteosclerosis and neuropathy-related disability, may not translate into higher risk of HDT as compared with classic multiple myeloma. After HDT, MIg was no longer detectable by immunofixation in the serum or urine of 4 patients. The other patient (case 3) achieved a very good response with disappearance of abnormal bone marrow infiltration and with normal serum electrophoresis, whereas the MIg was still detectable by serum immunofixation. In all patients, MIg was easily detectable before transplantation, and HDT likely played a crucial role in tumor mass reduction. The small number of patients precludes any definitive conclusion about the best high-dose therapeutic strategy (one or 2 HDT, with or without total body irradiation) to propose to patients with POEMS. In contrast, mobilizing PBSCs by growth factor alone might be more convenient than using high-dose cyclophosphamide, which potentially increases the risks of the procedure, whereas it did not produce significant tumor mass reduction in any of our patients, as assessed by follow-up of MIg level. In all cases, remission of plasma cell proliferation was associated with a marked improvement in performance and in neurologic symptoms (Table 2). Motor deficiency significantly improved, particularly in the tetraplegic patient who could walk again about 4 months after transplantation. Similarly, sensory disturbance improved in all cases, allowing, for instance, patient 3 to jog a few kilometers, whereas ataxia precluded running even a few meters before HDT. In all cases but one (case 2), initially abolished deep tendon reflexes reappeared. Electromyographic studies were repeated only in patient 5, who initially had isolated demyelinating lesions, and showed posttransplantation normalization of nerve conduction speeds. In addition to neurologic symptoms, other manifestations of the POEMS syndrome improved, especially skin changes, edema, papilledema, and organomegaly that was no longer detectable after transplantation in any case. Serum thyroid-stimulating hormone levels returned to normal value in the 2 patients with hypothyroidism, whereas the patient with adrenal insufficiency still needed low-dose hydrocortisone after transplantation. In the same patient, all symptoms related to POEMS nephropathy disappeared except hypertension. Within a median follow-up of 36 months since HDT, no patient experienced a relapse either of plasma cell dyscrasia or of related POEMS manifestations. Although still poorly understood, the pathogenesis of the POEMS syndrome may be related to production by the clonal plasma cells (or their environment) of a combination of soluble factors, resulting in increased vascular permeability and neoangiogenesis.14,15 Among various cytokines, vascular endothelial growth factor may have a pivotal role.16,17 We studied vascular endothelial growth factor serum levels in 2 patients (cases 1 and 2) by using an enzyme-linked immunosorbent assay adapted from Fixe et al.18 In both, pretreatment level was high (3684 and 2644 pg/mL, respectively, as compared with 471 (± 86) pg/mL in 37 healthy blood donors), and posttransplantation levels returned to normal (240 and 394 pg/mL 1 month after HDT, respectively). Although involving a small number of patients, this retrospective study shows the interest of HDT with stem cell support in patients with POEMS syndrome who present with multifocal bone lesions and/or diffuse plasmacytic bone marrow infiltration. In patients with a limited number of solitary plasmocytomas, radiation therapy probably remains the treatment of choice, but HDT should be studied in larger studies as an alternative, particularly when complete remission, including disappearance of the MIg, is not achieved or when relapse occurs.     Footnotes Submitted July 2, 2001; accepted November 22, 2001. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Jean-Paul Fermand, Service d'Immuno-Hématologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris cedex 10, France; e-mail: jpfermand{at}yahoo.fr.     References Top Abstract Introduction Study design Results and discussion References 1. Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology. 1984;34:712-720[Abstract/Free Full Text]. 2. Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes: the POEMS syndrome: report on two cases and a review of the literature. Medicine. 1980;59:311-322[Medline] [Order article via Infotrieve]. 3. Driedger H, Pruzanski W. Plasma cell neoplasia with peripheral polyneuropathy: a study of five cases and a review of the literature. Medicine. 1980;59:301-310[Medline] [Order article via Infotrieve]. 4. Soubrier M, Dubost JJ, Sauvezie B, and the French Study Group on POEMS Syndrome. POEMS syndrome: a study of 25 cases and a review of the literature. Am J Med. 1994;97:543-553[CrossRef][Medline] [Order article via Infotrieve]. 5. Miralles GD, O'Fallon JR, Talley NJ. Plasma-cell dyscrasia with polyneuropathy. The spectrum of POEMS syndrome. N Engl J Med. 1992;327:1919-1923[Abstract]. 6. Schey S. Osteosclerotic myeloma and POEMS syndrome. Blood Rev. 1996;10:75-80[CrossRef][Medline] [Order article via Infotrieve]. 7. Delauche MC, Clauvel JP, Seligmann M. Peripheral neuropathy and plasma cell neoplasias. Br J Haemat. 1981;48:383-392[Medline] [Order article via Infotrieve]. 8. Kelly JJ, Kyle RA, Miles JM, Dick PJ. Osteosclerotic myeloma and peripheral neuropathy. Neurology. 1983;33:202-210[Abstract/Free Full Text]. 9. Selby P, McElwain T, Nandi AC, et al. Multiple myeloma treated with high dose intravenous melphalan. Br J Haematol. 1987;66:55-62[Medline] [Order article via Infotrieve]. 10. Modesto-Segonds A, Rey JP, Orfila C, Huchard G, Suc JM. Renal involvement in POEMS syndrome. Clin Nephrol. 1995;43:342-345[Medline] [Order article via Infotrieve]. 11. Nakamoto Y, Imai H, Yasuda T. A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome. Nephrol Dial Transplant. 1999;14:2370-2378[Abstract/Free Full Text]. 12. Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol. 1998;101:766-769[CrossRef][Medline] [Order article via Infotrieve]. 13. Gertz MA, Lacy MQ, Gastineau DA, et al. Blood stem cell transplantation as therapy for primary systemic amyloidosis (AL). Bone Marrow Transplant. 2000;26:963-969[CrossRef][Medline] [Order article via Infotrieve]. 14. Gherardi RK, Belec L, Fromont G, et al. Elevated levels of interleukin-1 (IL-1) and IL-6 in serum and increased production of IL-1 mRNA in lymph nodes of patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome. Blood. 1994;83:2587-2593[Abstract/Free Full Text]. 15. Gherardi RK, Belec L, Soubrier M, et al. Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. Blood. 1996;87:1458-1465[Abstract/Free Full Text]. 16. Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet. 1996;347:702[Medline] [Order article via Infotrieve]. 17. Soubrier M, Dubost JJ, Serre AF, et al. Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor. Arthritis Rheum. 1997;40:786-787[Medline] [Order article via Infotrieve]. 18. Fixe P, Lorgeot V, Meur YL, et al. Development of enzymo-immunoassays (EIA) for macrophage colony-stimulating factor (M-CSF) and leukaemia inhibitory factor (LIF) by using the same capture and signal generating polyclonal antibody. Cytokine. 1996;8:586-591[CrossRef][Medline] [Order article via Infotrieve]. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: Long-term follow-up on a patient with incomplete POEMS syndrome undergoing high-dose therapy and autologous blood stem cell transplantation Anne Wiesmann, Robert Weissert, Lothar Kanz, and Hermann Einsele Blood 2002 100: 2679-2680. [Full Text] [PDF] This article has been cited by other articles: M Vermeulen and M H J van Oers Relapse of chronic inflammatory demyelinating polyneuropathy 5 years after autologous stem cell transplantation BMJ Case Reports, January 22, 2009; 2009(jan21_1): bcr0820080646 - bcr0820080646. [Abstract] [Full Text] S. Kuwabara, S. Misawa, K. Kanai, Y. Suzuki, Y. Kikkawa, S. Sawai, T. Hattori, M. Nishimura, and C. Nakaseko Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome Neurology, November 18, 2008; 71(21): 1691 - 1695. [Abstract] [Full Text] [PDF] C. Chalk Making the lame walk?: Transplantation for POEMS Neurology, November 18, 2008; 71(21): 1658 - 1659. [Full Text] [PDF] S Kuwabara, S Misawa, K Kanai, S Sawai, T Hattori, M Nishimura, and C Nakaseko Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome J. Neurol. Neurosurg. Psychiatry, November 1, 2008; 79(11): 1255 - 1257. [Abstract] [Full Text] [PDF] M Vermeulen and M H J van Oers Relapse of chronic inflammatory demyelinating polyneuropathy 5 years after autologous stem cell transplantation J. Neurol. Neurosurg. Psychiatry, October 1, 2007; 78(10): 1154 - 1154. [Abstract] [Full Text] [PDF] S. Kuwabara, S. Misawa, K. Kanai, Y. Kikkawa, M. Nishimura, C. Nakaseko, R. K. Cho, and T. Hattori Autologous peripheral blood stem cell transplantation for POEMS syndrome Neurology, January 10, 2006; 66(1): 105 - 107. [Abstract] [Full Text] [PDF] A. Dispenzieri POEMS Syndrome Hematology, January 1, 2005; 2005(1): 360 - 367. [Abstract] [Full Text] [PDF] A. Dispenzieri, A. Moreno-Aspitia, G. A. Suarez, M. Q. Lacy, G. Colon-Otero, A. Tefferi, M. R. Litzow, V. Roy, W. J. Hogan, R. A. Kyle, et al. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature Blood, November 15, 2004; 104(10): 3400 - 3407. [Abstract] [Full Text] [PDF] A. Dispenzieri, R. A. Kyle, M. Q. Lacy, S. V. Rajkumar, T. M. Therneau, D. R. Larson, P. R. Greipp, T. E. Witzig, R. Basu, G. A. Suarez, et al. POEMS syndrome: definitions and long-term outcome Blood, April 1, 2003; 101(7): 2496 - 2506. [Abstract] [Full Text] [PDF] A. Wiesmann, R. Weissert, L. Kanz, and H. Einsele Long-term follow-up on a patient with incomplete POEMS syndrome undergoing high-dose therapy and autologous blood stem cell transplantation Blood, September 18, 2002; 100(7): 2679 - 2680. [Full Text] [PDF] S. Kuwabara, S. Misawa, K. Kanai, Y. Kikkawa, M. Nishimura, C. Nakaseko, R. K. Cho, and T. Hattori Autologous peripheral blood stem cell transplantation for POEMS syndrome Neurology, January 10, 2006; 66(1): 105 - 107. 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