Successful Treatment of POEMS Syndrome Complicated by Severe Congestive Heart Failure with Thalidomide

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1 CASE REPORT Successful Treatment of POEMS Syndrome Complicated by Severe Congestive Heart Failure with Thalidomide Daichi Inoue 1,AikoKato 1, Sumie Tabata 1, Takeshi Kitai 2, Yoko Takiuchi 1, Takaharu Kimura 1, Sonoko Shimoji 1,MinakoMori 1, Yuya Nagai 1, Katsuhiro Togami 1, Akiko Matsushita 1, Kenichi Nagai 1, Hayato Maruoka 3, Yukihiro Imai 4, Minako Beppu 5, Michi Kawamoto 5 and Takayuki Takahashi 1 Abstract A 55-year-old woman was diagnosed with POEMS syndrome; however, we could not perform high-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-pbsct) because of rapidly progressive congestive heart failure. Thus, we treated the patient with thalidomide plus dexamethasone, which brought about a marked improvement of systolic dysfunction, POEMS syndrome-related symptoms and the serum concentrations of vascular endothelial growth factor. Subsequently, we safely performed high-dose chemotherapy with auto-pbcst. This report strongly suggests that thalidomide is effective for POEMS syndrome, even if complicated by congestive heart failure which is considered to be related to POEMS syndrome. Key words: POEMS syndrome, thalidomide, congestive heart failure, VEGF (Inter Med 49: , 2010) () Introduction POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome is a rare multisystem disorder with a poor prognosis (1, 2). Although the pathogenesis is not completely understood, the overproduction of a variety of cytokines such as vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α is likely responsible for most of the characteristic symptoms (3, 4). Notably, almost all patients with POEMS syndrome exhibit highly elevated serum VEGF levels, and the disease activity appears to be correlated with these levels. Dispenzieri proposed revised criteria of POEMS syndrome, that is, polyneuropathy, monoclonal plasma cell proliferative disorder, elevation of blood VEGF levels, sclerotic bone lesions, and Castleman disease as major criteria; organomegaly, edema, endocrinopathy, skin changes, papilloedema, thrombocytosis, and/or polycythemia as minor criteria (5). Although conventional therapies including corticosteroids and melphalan exhibit a transient effect (6), high-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-pbsct) has been recommended in suitable cases, because it brings about clear improvements of neuropathy as well as other symptoms with a significant decrease in the serum VEGF levels (7, 8). In recent years, thalidomide therapy has been employed in some patients unsuitable for high-dose chemotherapy with auto-pbsct owing to their age and organ failure (9-11). Herein, we report a patient with POEMS syndrome complicated by severe congestive heart failure (CHF) due to systolic dysfunction and successful treatment with thalidomide followed by high-dose chemotherapy with auto-pbcst. Department of Hematology and Clinical Immunology, Kobe City Medical Center General Hospital, Kobe, Department of Cardiology, Kobe City Medical Center General Hospital, Kobe, Department of Clinical Laboratory, Kobe City Medical Center General Hospital, Kobe, Department of Clinical Pathology, Kobe City Medical Center General Hospital, Kobe and Department of Neurology, Kobe City Medical Center General Hospital, Kobe Received for publication August 31, 2009; Accepted for publication November 13, 2009 Correspondence to Dr. Takayuki Takahashi, sonata53@kcgh.gr.jp 461

2 Table1. LaboratoryFindingsonAdmision Case Report A previously healthy 55-year-old woman was referred to a hospital in August 2008 because of progressive edema. POEMS syndrome was suspected based on hepatosplenomegaly, fingernail clubbing, skin changes including multiple hemangiomas and hypertricosis, and high-level serum VEGF. She was introduced to our hospital in November 2008 for the purpose of a precise diagnosis and possible high-dose chemotherapy. Physically, marked pitting edema of the bilateral legs and ascites were noted in addition to the other physical signs described as above. Chest X-P showed massive pleural and pericardial effusion. A nerve conduction examination demonstrated mild polyneuropathy such as lowamplitude M waves, the disappearance of F waves, and delayed nerve conduction of the lower extremities. Laboratory findings are shown in Table 1. Hematological examination showed a white blood cell count of /L with a normal differential count, a hemoglobin concentration of 10.6 g/dl, and a platelet count of /L. Serum VEGF and brain natriuretic peptide (BNP) concentrations were markedly elevated to 16,300 pg/ml (normally less than 38.3 pg/ ml) and 1,165 pg/ml (normally less than 18.4 pg/ml), respectively. Although a bone marrow aspirate disclosed a slightly increased number of mature plasma cells comprising 5% of total nucleated cells, we could not demonstrate the monoclonality of the plasma cells using flow cytometry and PCR with BIOMED-2 primer sets to detect clonal immunoglobulin heavy chain rearrangements (12). We also could not detect serum M-protein using immunoelectrophoresis and immunofixation. Flow cytometry demonstrated that these plasma cells were positive for CD 19, 38, and 138 and did not exhibit κ/λ restriction, which was also confirmed by the immunohistochemistry. Surprisingly, echocardiography revealed diffuse severe hypokinesis of the left ventricle (LV), with only 28% of the ejection fraction (EF) and slightly dilated LV (Fig. 3). The hypokinesis had not been noted on echocardiography performed in the previous hospital a month earlier. Cardioangiography showed no lesion of the coronary arteries. We subsequently performed endomyocardial biopsy of the right ventricle. Histologically, moderate hypertrophy, vacuolation, and bizarre pattern of myocytes, and irregular nuclei were observed (Fig. 1). Amyloid deposition was not noted and staining for VEGF receptor (FLK-1) yielded a negative result. Although we could not detect monoclonal plasma cell proliferation, we made a diagnosis of POEMS syndrome on the basis of findings described as above. We considered that high-dose chemotherapy was very risky because of severe CHF. Therefore, we treated her with thalidomide (100 mg/ day, increased to 200 mg 14 days later) plus intravenous dexamethasone (20 mg/ day for 4 consecutive days, repeated every 10 days) (Fig. 2), on obtaining written informed consent under the approval of our institutional review board. This treatment rapidly resolved her CHF and markedly improved all markers of cardiac function such as body weight, EF, and BNP within a month. Interestingly, the serum VEGF levels rapidly decreased along with the improvement of her CHF. We also confirmed the marked recovery of impaired nerve conduction and abnormal endocrine markers. Thalidomide treatment was well tolerated except for constipation. We then collected peripheral blood stem cells using granulocyte colony-stimulating factor in January 2009, because we worried that cyclophosphamide would exhibit cardiac toxicity. We harvested /kg CD34 + cells, and then 462

3 Figure1. Histologicanalysesofbiopsiedendomyocardium oftherightventricle.a:histologic pictureofthemyocardium;hematoxylinandeosinstaining, 400.Moderatehypertrophy,vacuo lation,andirregularnucleiofmyocyteswereobserved.b:hematoxylinandeosinstaining, 100. Amildbizarrepaternofmyocyteswasnoted.C:Mason sstaining, 100.Mildinterstitialfibrosis oftherightventriclewasseen. Figure2. Clinicalcourseofthepresentpatient.Thalidomidetherapymarkedlyresolvedconges tiveheartfailure,withtherapidimprovementofalmarkerssuchasbodyweight,ef,andbnp withinamonth.serum VEGFlevelsalsorapidlydecreasedalongwithimprovementofthecardiac function.dex:dexamethasone,pbsch:peripheralbloodstem celharvest,mel:melphalan, PBCST:peripheralbloodstem celtransplantation,ef:ejectionfraction performed high-dose chemotherapy (melphalan of 200 mg/m 2 ) with auto-pbsct in February Stable and durable neutrophil engraftment was achieved from day 10 onwards. She was discharged on day 16 without any complications including infection, engraftment syndrome, and the recurrence of CHF. POEMS syndrome did not flare up until September 2009, and she currently maintains a favorable condition. 463

4 Figure3. Cardiacfunctionsbeforeandafterthalidomidetherapy.Leftventricularejectionfractionincreasedfrom 28% to50% andthevolumeofpericardialefusiondecreased,asevaluatedby echocardiographyfrom para-sternallongaxisviewatenddiastole(a,c)andendsystole(b,d) justbeforetheadministrationofthalidomideinnovember2008,and2weeksaftertheinitiationof thalidomidetherapy,respectively.cardiomegalyandpulmonarycongestiondisappearedasshown inchestradiographbefore(e)andafter(f)thalidomidetherapy.electrocardiogram beforethalidomidetreatment(g)demonstratednon-specificdamageofthemyocardium withleftanterior hemiblock,poorrprogresioninleadsv2andv3,andnegativet-waveinleadsv4andv6.with thalidomidetreatmentthesefindingsreturnedtonormalpaterns. Discussion Regarding the diagnosis of POEMS syndrome, we were unable to detect the monoclonality of plasma cells in the present patient. Free light chain assays of the serum may help to detect faint M-protein, although we did not perform such assays. However, the diagnosis of POEMS syndrome appears definitive because of many findings specific or related to this syndrome such as polyneuropathy, organomegaly, pitting edema, skin changes, endocrinopathy, extremely high serum VEGF levels. In the criteria for the diagnosis of POEMS syndrome, which was advocated by Dispenzieri (5), the present patient met 2 of 5 major criteria and 4 of 6 minor criteria. Furthermore, the clinical picture of the present patient and extremely high serum concentrations of VEGF (>10,000 pg/ml) do not meet any clinical entities other than POEMS syndrome. Therefore, whether the monoclonality is truly essential for the diagnosis of PO- EMS syndrome should be reevaluated with the accumulation of cases similar to ours. Nakaseko et al in Chiba University (Chiba, Japan) have recently encountered 2 cases of POEMS syndrome without the monoclonality even when examined with immunofixation (personal communication). We suppose that proliferated polyclonal plasma cells might have produced POEMS syndrome-related cytokines and subsequently lead to this disorder, because the percentage of marrow plasma cells returned to be within normal limits (0.2% of total nucleated cells) after thalidomide treatment. Immunostaining of the bone marrow clot specimen for VEGF would support our hypothesis; however, materials for the staining are currently not available. Although the major purpose of high-dose chemotherapy with auto-pbsct for PO- EMS syndrome seems to purge the clonal plasma cells, we consider the rationale for employing it in this case lies in eliminating the bulk of abnormal plasma cells that might have produced VEGF and other pathogenic cytokines and in resetting the abnormal cytokine network through its transient ablation. Serum VEGF continuously decreased after highdose chemotherapy may support the rationale. Of interest, severe dysfunction of the myocardium was observed in the present patient. The relationship between it and POEMS syndrome has been reported in 6 patients in the literature, as shown in Table 2 (13-18). Dispenzieri et al reviewed 99 cases of POEMS syndrome, and of these, 3 cases were associated with CHF at presentation and 4 patients de- 464

5 Table2. ReportsofPOEMSSyndromeComplicatedbyCongestiveHeartFailure Patients No. Sex Age POEMS features P O E M S Other features Cardiac disorder Echocardiography CAG Bipopsy Outcomes Reference 1 F 51 P O E M S Sclerotic Cardiomegaly LV dilatation, Hypokinesis Normal Chemotherapy [13] 2 M 60 O M S Sclerotic Mild cardiomegaly Marked hypertrophy Normal Hypertrophic cardiomyopathy [14] 3 M 31 P O E M S CHF, Cardiomegaly LV dilatation, Hypokinesis Stenosis diffuse and multiple Ischemic cardiomyopathy Resection of plasmacytoma [15] 4 M 45 P O M Sclerotic CHF, Cardiomegaly Radiation and chemotherapy [16] 5 F 60 P O S Papilledema, Mild cardiomegaly Moderate hypertrophy, Pulmonary hypertension Mild fibrosis PSL [17] 6 M 27 P O E M S Sclerotic Mild cardiomegaly LV dilatation, Hypokinesis Stenosis diffuse and multiple PSL [18] P: polyneuropahty; O: organomegaly; E: endocrinopathy; M: M protein; S: skin changes CHF: congestive heart failure; LV: left ventricle; CAG: coronary angiography; PSL: prednisolone. veloped CHF with the progression of POEMS syndrome (2). Although the relationship has not been fully elucidated, marked improvement of CHF has been reported along with the treatment of POEMS syndrome in most of these patients (13, 15-18). As the pathogenesis of CHF in these patients, ischemic or hypertrophic cardiomyopathy has been suggested in previous reports (14, 15, 18). In the present patient, we observed the rapid progression of CHF with the activity of POEMS syndrome and marked improvement following thalidomide treatment. Although we could not detect coronary artery injury or up-regulated VEGF receptors in small blood vessels of the heart, we considered that CHF was POEMS syndrome-related, because she showed no history of heart disease, and the histologic picture of the biopsied specimen ruled out amyloidosis, sarcoidosis, eosinophilic or viral myocarditis, and alcoholic cardiomyopathy. The result of the biopsy just indicated non-specific damage of the myocardium in regeneration state, whereas the damage was not chronic from the viewpoint of the fibrosis. VEGF has been shown to exert multiple biological effects on the epithelium, causing potent and rapid induction of microvascular hyperpermeability, extravasation of fibrinogen and coagulation factors, and the production of plasminogen activators and plasminogen activator inhibitor-1 by endothelial cells (19, 20). We suspect that the extremely high level of VEGF was responsible for the impairment of microcirculation, which may have lead to the acute systolic dysfunction of LV. While high-dose chemotherapy with auto-pbsct has been shown to be an efficacious treatment for POEMS syndrome, several reports have suggested the efficacy of thalidomide (9-11), lenalidomide (21), and bevacizumab (anti- VEGF monoclonal antibody) (22) for elderly patients or those with organ dysfunction. Thalidomide, which is becoming a promising agent for POEMS syndrome, has antiangiogenic, anti-inflammatory, and immunomodulatory actions and has been successfully used in the treatment of multiple myeloma (23). Kuwabara et al reported that thalidomide therapy resulted in the marked clinical improvement or stabilization of POEMS-related neuropathy and a significant decrease in serum VEGF concentrations in all 9 patients treated with this agent without serious adverse effects including neuropathy (11). In the present patient, it is notable that we achieved the marked improvement of cardiac function, including that of high BNP, low EF, and systolic dysfunction, and other POEMS syndrome-related symptoms. Thalidomide may have rapidly controlled abnormally secreted cytokines such as VEGF, because steroid monotherapy has been shown to exhibit limited efficacy for POEMS syndrome (24). Furthermore, thalidomide treatment in the present patient, in accordance with a previous report (25), did not have a serious impact on the collection of stem cells and also did not induce neuropathy. We performed auto-pbsct following thalidomide therapy considering the possible adverse effects and unknown long-term disease control with thalidomide monotherapy. Ohwada et al have recently reported successful combination treatment with bevacizumab, thalidomide and auto-pbsct for severe 465

6 POEMS syndrome (26). In conclusion, we successfully treated POEMS syndrome complicated by rapidly progressive CHF, which was considered to be POEMS syndrome-related. Thalidomide appears to be a promising agent for POEMS syndrome even when complicated by CHF, and the accumulation of similar cases is necessary to clarify the pathogenesis of associated CHF in this syndrome. References 1. Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 34: , Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood 101: , Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in PO- EMS syndrome. Lancet 347: 702, Feinberg L, Temple D, de Marchena E, Patarca R, Mitrani A. Soluble immune mediators in POEMS syndrome with pulmonary hypertension: case report and review of the literature. Crit Rev Oncog 10: , Dispenzieri A. POEMS syndrome. Blood Rev 21: , Kuwabara S, Hattori T, Shimoe Y, Kamitsukasa I. Long term melphalan-prednisolone chemotherapy for POEMS syndrome. J Neurol Neurosurg Psychiatry 63: , Kuwabara S, Misawa S, Kanai K, et al. Autologous peripheral blood stem cell transplantation for POEMS syndrome. Neurology 66: , Dispenzieri A, Moreno-Aspitia A, Suarez GA, et al. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood 104: , Sinisalo M, Hietaharju A, Sauranen J, Wirta O. Thalidomide in POEMS syndrome: case report. Am J Hematol 76: 66-68, Kim SY, Lee SA, Ryoo HM, Lee KH, Hyun MS, Bae SH. Thalidomide for POEMS syndrome. Ann Hematol 85: , Kuwabara S, Misawa S, Kanai K, et al. Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome. J Neurol Neurosurg Psychiatry 79: , van Dongen JJ, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT Leukemia 17: , Tanus T, Miller HJ. POEMS syndrome presenting with cardiomegaly and cardiomyopathy. J Intern Med 231: , Shimizu N, Goya M, Akimoto H, et al. Cardiomyopathy in a case of Crow-Fukase syndrome. Jpn Heart J 38: , Ichikawa Y, Nakata T, Ohhata J, et al. Crow-Fukase syndrome with ischemic cardiomyopathy. Intern Med 40: , Reitan JB, Pape E, Fosså SD, Julsrud OJ, Slettnes ON, Solheim OP. Osteosclerotic myeloma with polyneuropathy. Acta Med Scand 208: , Iwasaki H, Ogawa K, Yoshida H, et al. Crow-Fukase syndrome associated with pulmonary hypertension. Intern Med 32: , Manning WJ, Goldberger AL, Drews RE, et al. POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature. Semin Arthritis Rheum 22: , Shen H, Clauss M, Ryan J, et al. Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes. Blood 81: , Senger DR. Molecular framework for angiogenesis: a complex web of interactions between extravasated plasma proteins and endothelial cell proteins induced by angiogenic cytokines. Am J Pathol 149: 59-71, Dispenzieri A, Klein CJ, Mauermann ML. Lenalidomide therapy in a patient with POEMS syndrome. Blood 110: , Samaras P, Bauer S, Stenner-Liewen F, et al. Treatment of PO- EMS syndrome with bevacizumab. Haematologica 92: , Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21: 16-19, Henze T, Krieger G. Combined high-dose 7S-IgG and dexamethasone is effective in severe polyneuropathy of the POEMS syndrome. J Neurol 242: , Breitkreutz I, Lokhorst HM, Raab MS, et al. Thalidomide in newly diagnosed multiple myeloma: influence of thalidomide treatment on peripheral blood stem cell collection yield. Leukemia 21: , Ohwada C, Nakaseko C, Sakai S, et al. Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome. Bone Marrow Transplant 43: , The Japanese Society of Internal Medicine 466