POEMS syndrome demonstrating VEGF decrease by ticlopidine

POEMS syndrome is a syndrome that presents with polyneuropathy, organomegaly, endocrinopathy, M-proteins and skin changes. Elevated vascular endothelial growth factor (VEGF) has recently been reported in POEMS syndrome. We report a case of POEMS syndrome with high VEGF titers. Steroid, plasmapheresis and intravenous gamma-globulin had little effect. Various immunosuppressive agents were discontinued due to side effects. Although administration of aspirin did not decrease VEGF, ticlopidine decreased VEGF significantly. This case suggests that ticlopidine is a candidate for supportive therapy in POEMS syndrome and we should measure VEGF before and after the administration of ticlopidine in other cases.     

The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome

The POEMS syndrome is associated with elevated vascular endothelial growth factor (VEGF) levels. Several studies have compared serum VEGF levels between POEMS patients and other disease entities showing higher serum VEGF in POEMS syndrome; however, it is unknown whether serum levels are reliable and reproducible given variable platelet release of VEGF. We therefore compared plasma levels of VEGF in 29 patients with POEMS syndrome with those of other disorders (n = 76). We demonstrated that plasma VEGF levels are useful in differentiating POEMS from other plasma cell dyscrasias, neuropathic processes, and multisystem illnesses. Plasma VEGF is also useful in monitoring disease activity after treatment and correlates with clinical improvements better than hematologic response.     

Borderline Case of TAFRO Syndrome and POEMS Syndrome

TAFRO syndrome and POEMS syndrome are lymphoproliferative disorders with elevated interleukin-6 and vascular endothelial growth factor (VEGF) levels; however, their underlying pathogenic mechanisms remain unclear. Similarities have been reported in the pathological findings of the lymph nodes of TAFRO syndrome, Multicentric Castleman disease (MCD), and some cases of POEMS syndrome. However, there is no consensus on the relationship among them. We encountered a case of lymphoproliferative disorder that presented with manifestations of both TAFRO syndrome and POEMS syndrome. This case may be a subtype of idiopathic MCD and will be very important for establishing the disease concept of TAFRO syndrome and POEMS syndrome.     

Ratio of serum vascular endothelial growth factor to platelet count correlates with disease activity in a patient with POEMS syndrome

Vascular endothelial growth factor (VEGF) is known to be involved in the pathogenesis of POEMS (polyneuropathy, organomegaly, endocrine disorder, M-protein, and skin lesion) syndrome. Because platelets have recently been recognized as transporters of VEGF, enhanced blood coagulation activity in this syndrome may accelerate vasopermeability by releasing VEGF from platelets in vivo. Here we report a case of POEMS syndrome with anasarca showing a high ratio of serum VEGF to platelet count, indicative of massive VEGF release from aggregated platelets in vivo. Changes in the ratio clearly reflected disease activity. This observation suggests that the ratio of serum VEGF to platelet count is more precise in monitoring disease activity than serum VEGF alone, and that VEGF released in vivo is critically involved in the pathogenesis of POEMS syndrome, causing hypervasopermeability.     

Multiple angiogenetic factors are upregulated in POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem disorder associated with plasma cell dyscrasia. Elevated serum levels of vascular endothelial growth factor (VEGF), which strongly promotes neovascularization and vasopermeability, are considered to be responsible for the characteristic symptoms such as angiomata, pleural effusion/ascites, edema, and organomegaly in the disorder. To study whether other angiogenetic factors are upregulated in POEMS syndrome, we measured serum levels of basic fibroblast growth factor and hepatocyte growth factor (HGF), as well as VEGF, in 17 patients with POEMS syndrome. All these factors were significantly upregulated in the POEMS syndrome patients. After the treatment with anti-VEGF antibody, the levels of HGF did not change, suggesting that elevation of HGF levels is not secondary to VEGF overproduction. These results suggest that different angiogenetic factors might contribute to the pathogenesis of POEMS syndrome, and this fact might contribute to the insufficient clinical effects obtained by suppression of VEGF alone.     

Development of POEMS syndrome after an initial manifestation of solitary plasmacytoma

A 44-year-old male was admitted for numbness in the left arm. CT showed a tumor impacting on the spinal cord with an adjacent thoracic vertebral osteosclerotic lesion. The histopathology of the tumor showed diffuse proliferation of atypical plasma cells with expressed vascular endothelial growth factor (VEGF), which is a known etiological factor in POEMS syndrome. Though serum VEGF (sVEGF) level was elevated, a diagnosis of solitary plasmacytoma with an osteosclerotic lesion was made as the patient presented no polyneuropathy, organomegaly, endocrinopathy, or skin changes. The patient experienced muscle weakness of the lower limbs and skin pigmentation/hemangioma one year after irradiation of the osteosclerotic lesion. Laboratory tests revealed hypothyroidism, hyperglycemia, serum monoclonal gammopathy, further elevation of sVEGF, and increased atypical bone marrow plasma cells. CT imaging showed splenomegaly, and a nerve conduction test revealed demyelinating motor peripheral neuropathy. The patient was therefore diagnosed with POEMS syndrome. Plasmacytoma is very rare as an initial manifestation of POEMS syndrome. Patients presenting with plasmacytoma with an osteosclerotic lesion should be carefully observed and evaluated for the expression of sVEGF and development of POEMS syndrome, as most bone plasmacytomas in POEMS syndrome patients are reported to be osteosclerotic. This is to our knowledge the first case of osteosclerotic plasmacytoma that progressed to POEMS syndrome, with an increase of sVEGF.     

VEGF is causative for pulmonary hypertension in a patient with Crow-Fukase (POEMS) syndrome

We report a case of Crow-Fukase (POEMS) syndrome associated with pulmonary hypertension (PH). In this case, the concentration of vascular endothelial growth factor (VEGF) was extremely high in the serum, and the levels of IL-1beta, IL-6, TNF-alpha, and thiamine, which were thought in past reports to be mediators of PH in Crow-Fukase syndrome, were normal. After prednisolone therapy, PH disappeared with a dramatic decrease in serum VEGF. Our results suggest that VEGF is closely correlated with PH in Crow-Fukase syndrome.     

Treatment of POEMS syndrome with bevacizumab

We report a case of POEMS syndrome which relapsed six years after autologous peripheral blood stem cell transplantation. According to encouraging data published recently, we treated the patient with cyclophosphamide, dexamethasone and the VEGF-antibody bevacizumab. After an initial improvement, the subsequent course was complicated by severe adverse events leading to multiorgan failure and death. This dramatic decline highlights the need for further investigation before using bevacizumab in patients with POEMS syndrome.     

POEMS syndrome diagnosed by detection of M-protein on immunofixation and increased level of vascular endothelial growth factor

A 48-year-old male with Castleman disease developed symptoms typical of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal-protein and skin changes) but M-protein was not detected by immunoelec-trophoresis. He was diagnosed as having POEMS syndrome based on IgA-λ detected by immunofixation electrophoresis and an increased level (3,170 pg/ml) of vascular endothelial growth factor (VEGF). After diagnosis, the patient underwent autologous peripheral blood stem cell transplantation safely and remained relapse-free and in good condition for 15 months. This case suggests that immunofixation electrophoresis and detection of elevated serum VEGF level are useful methods for earlier diagnosis of POEMS syndrome.     

Pachymeningeal involvement in POEMS syndrome: dramatic cerebral MRI improvement after lenalidomide therapy

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare multisystemic disease associated with plasma cell dyscrasia and increased serum or plasma vascular endothelial growth factor (VEGF) levels, the latter likely responsible for several POEMS syndrome manifestations. Whereas peripheral neuropathy is the main neurological feature and a mandatory diagnostic criterium, central nervous system involvement is less common except for papilledema and stroke. We recently reported the frequent occurrence at brain MRI of cranial pachymeningeal involvement ina series of POEMS syndrome patients. Meningeal histopathology revealed hyperplasia of meningothelial cells, neovascularization, and obstructive vessel remodeling without inflammatory signs pointing to a role of VEGF in the meningeal manifestations. Here, we report the dramatic pachymeningeal improvement in patients undergoing lenalidomide therapy. These findings support the therapeutic role of lenalidomide and might shed further light on the pathophysiology of the disease     

POEMS综合征血清血管内皮生长因子检测意义

目的探讨血清血管内皮生长因子(VEGF)在POEMS综合征中的临床意义。方法采用ELISA方法检测POEMS综合征组(36例)、疾病对照组(多发性骨髓瘤29例、格林巴利综合征7例共36例)、正常对照组(36例)的血清VEGF浓度,进行组间比较,并与临床资料进行相关性分析。结果 POEMS综合征组血清VEGF浓度为(982.06±611.49)pg/ml,显著高于疾病对照组[(364.22±264.37)pg/ml]和正常对照组[(217.37±87.74 pg/ml)],P<0.001。VEGF诊断POEMS综合征曲线下面积为0.902,VEGF Cutoff值为360.62 pg/ml,敏感性为0.889,特异性为0.764。POEMS综合征组血清VEGF与肺动脉高压、外周血小板计数相关,与其他临床表现无显著相关性。结论血清VEGF浓度升高是POEMS综合征的一个重要特征,有助于POEMS综合征的诊断;血清VEGF浓度与肺动脉高压有一定相关性,可能是肺动脉高压发病机制之一。     

Primary cutaneous diffuse large B‐cell lymphoma,leg type,with features simulating POEMS syndrome

A 91‐year‐old woman presented with a rapidly proliferative cutaneous lesion on the left lower limb, which was identified as a primary cutaneous diffuse large B‐cell lymphoma (PCLBCL), leg type, on biopsy. The patient also showed complications of hepatomegaly, endocrinopathy, edema, skin change, and polyneuropathy without monoclonal plasma cell proliferative disorder, and was therefore diagnosed with POEMS‐like syndrome owing to the lack of monoclonal plasma cell proliferative disorder. Levels of serum vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) were high with the lymphoma cells immunostained positively for VEGF and IL‐6. To the best of our knowledge, this is the first case report of PCLBCL, leg type, with POEMS‐like syndrome. The findings in this case suggest that the symptoms of POEMS‐like syndrome might be caused by the cytokines produced by the lymphoma cells. Furthermore, a wider range of diagnostic criteria associated with the result of abnormal secretion of cytokine may have to be considered for the diagnosis and evaluation of patients with possible POEMS syndrome, as against the present criteria specifying monoclonal plasma cell proliferative disorder as the essential criterion.     

Predictive value of serial platelet count and VEGF determination for the management of DIC in the Crow-Fukase (POEMS) syndrome

We report a case of a 62-year-old man diagnosed as Crow-Fukase syndrome (POEMS syndrome), in which the serial platelet count and vascular endothelial growth factor (VEGF) concentration were determined before and during the state of disseminated intravascular coagulation (DIC). The serum VEGF concentration was noted to be gradually decreased prior to DIC, after which it abruptly decreased with a corresponding drop in platelet count upon the onset of DIC. The physiological effects of VEGF are viewed as one of the causative factors in DIC and its abrupt and excessive release may have caused the exacerbation of the patient's clinical symptoms.     

Successful treatment of POEMS syndrome with bortezomib and dexamethasone, combined with radiotherapy, and followed by autologous stem cell transplantation

POEMS syndrome is a monoclonal plasma cell disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are an effective therapy, but optimal treatment options are still under debate. Bortezomib is an important agent for the treatment of patients with multiple myeloma and has recently been reported as efficacious in the treatment of patients with POEMS syndrome. We present a case of POEMS syndrome in a 33-year-old woman, who was successfully treated with BorDex (bortezomib and dexamethasone) combined with radiotherapy, and followed by ASCT. She was diagnosed with POEMS syndrome with a localized plasmacytoma of bone 5 months after her initial symptoms of heart failure. Her Eastern Cooperative Oncology Group (ECOG) performance status was 4. She was first administered BorDex therapy, which was subsequently combined with radiotherapy. Her general condition including heart failure dramatically improved after four cycles of BorDex therapy and radiation, resulting in partial response. After chemoradiotherapy, HDT and ASCT were performed. After treatment, she was able to walk unassisted and her plasma endothelial growth factor (VEGF) level decreased. She did not experience neurotoxicity induced by bortezomib. Bortezomib was well tolerated and we suggest that BorDex therapy followed by HDT and ASCT may be an effective therapy for POEMS syndrome.     

POEMS Syndrome with Biclonal Gammopathy and Renal Involvement

Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin changes (POEMS) syndrome manifests as elevated levels of vascular endothelial growth factor (VEGF) and monoclonal gammopathy. We treated a case of POEMS syndrome showing monoclonality in both IgA-λ and IgG-κ. Serial renal biopsies before treatment and after normalization of the VEGF levels suggested that glomerular microangiopathy had developed due to VEGF, while biclonal gammopathy was not eliminated. The renal pathology, proteinuria, and renal function all clearly improved. Although severe polyneuropathy limited activities of daily living and enforced a bedridden state, the patient dramatically regained his motor function, achieving crutch walking after induction of remission. This case is highly notable due to the presence of biclonality and repeated biopsies.     

Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem-cell transplantation

POEMS syndrome is a rare paraneoplastic condition associated to an underlying plasmacellular dyscrasia. The pathogenesis of POEMS is poorly understood, but overproduction of VEGF, probably secreted by clonal plasma cells, is thought to be responsible for the signs and symptoms of the syndrome, and it seems to be useful for the monitoring of the response to therapy. At present, an effective therapeutic option for the patients is represented by autologous peripheral blood stem-cell transplantation (aPBSCT), although relapses have been described, and there is an important morbidity associated with this procedure. Before the implementation of aPBSCT, the clinical course of POEMS syndrome was characterized by progressive polyneuropathy potentially leading to death for respiratory failure. Given the high serum and plasma levels of VEGF observed in POEMS patients, the use of anti-angiogenetic drugs such as thalidomide and lenalidomide and other drugs with anti-VEGF and anti-TNF effect such as bortezomib have been considered to treat this syndrome. There are evidences of lenalidomide benefit in both front-line and previously treated patients, but scanty data are available about its use for relapse after aPBSCT. Here, we report the successful use of lenalidomide in a patient who relapsed after aPBSCT.     

POEMS syndrome: A multisystem clonal disorder

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome is a rare condition defined by monoclonal plasma cell disorder, peripheral neuropathy, and other systemic symptoms. The pathophysiology of POEMS syndrome is unknown, but the overproduction of vascular endothelial growth factor (VEGF) appears to be an important contributory element. The diagnosis of POEMS syndrome requires the presence of both mandatory criteria (ie, polyneuropathy and a monoclonal plasma cell disorder), at least one major criterion (ie, osteosclerotic bone lesions, Castleman disease, or elevated serum or plasma levels of vascular endothelial growth factor), and at least one of the six minor criteria. POEMS syndrome lacks a standard treatment, but patients with limited sclerotic bone lesions are typically treated with radiation therapy. In contrast, those with widespread lesions receive chemotherapy and hematopoietic stem cell transplantation.     

Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome

Polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome is a devastating syndrome, characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells, skin changes, papilledema, volume overload, sclerotic bone lesions, thrombocytosis and high vascular endothelial growth factor (VEGF). High-dose chemotherapy with autologous peripheral blood stem cell transplantation (ASCT) ultimately yields excellent clinical responses, but there can be considerable peritransplant morbidity. We have treated 30 POEMS patients with ASCT at Mayo Clinic, Rochester. During transplant period, patients had high rates of fever, diarrhea, weight gain and rash (93%, 77%, 53% and 43%, respectively). Only 13% remained outpatient, and median time to discharge from hospital was transplant day 17 (range 0-175). Splenomegaly was the baseline factor that best predicted for a complicated peritransplant course. Depending on the definition used, approximately 50% of patients satisfied criteria for engraftment syndrome. Earlier and more aggressive use of corticosteroids may be associated with less complicated post-transplant courses. Median overall survival has not been reached; the treatment-related mortality was 3%. In addition, important clinical improvements and reductions in plasma VEGF levels can occur in the absence of significant decrease in the monoclonal protein. Unraveling the mechanisms of the syndrome both in the context of ASCT and in general are challenges for the future.     

A prospective phase II study of low dose lenalidomide plus dexamethasone in patients with newly diagnosed polyneuropathy,organomegaly, endocrinopathy,monoclonal gammopathy,and skin changes (POEMS) syndrome

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma dyscrasia without standard treatment. This phase II prospective trial evaluates the safety and response of 12 cycles of low dose lenalidomide (10 mg) plus dexamethasone (Rdex) in patients with newly diagnosed POEMS syndrome. Forty‐one patients (28 men) were enrolled and the median age at diagnosis was 49 years (range, 21‐70 years). Twenty‐one patients (46%) achieved complete hematologic response and the neurologic response rate was 95%. The median serum vascular endothelial growth factor (VEGF) declined from 5155 pg/mL (range, 534‐14 328 pg/mL) to 832 pg/mL (95‐6254 pg/mL) after therapy. The overall VEGF response rate was 83%, and the median time to response was 2 months, with a mean VEGF reduction of 43% at the first month. In terms of clinical response, Rdex substantially relieved extravascular volume overload, organomegaly, and pulmonary hypertension. No treatment‐related deaths occurred and no patients suffered from lenalidomide‐related grade 3 or above adverse events. After a median follow‐up of 34 months, median overall survival (OS) and progression‐free survival (PFS) were not reached, with an estimated 3‐year OS and PFS of 90% and 75%, respectively. In conclusion, Rdex was active with high hematologic, VEGF and organ response rate and well tolerated for patients with newly diagnosed POEMS syndrome. This trial was registered at www.clinicaltrials.gov as #NCT01816620.     

POEMS syndrome presenting with transient immunoglobulin isotype switching after successful treatment with autologous peripheral blood stem cell transplantation

A 60-year-old man was admitted with muscle weakness and numbness in the extremities. Based on the existence of monoclonal gammopathy of the IgG-lamda type, a slight increase of plasma cells in the bone marrow, and an elevated level of serum vascular endothelial growth factor (VEGF), the diagnosis of POEMS syndrome was made. After peripheral blood stem cell collection by etoposide and G-CSF, the patient received high dose melphalan (200 mg/m2) therapy supported by autologous peripheral blood stem cell transplantation (autoPBSCT). After high-dose chemotherapy with autoPBSCT, the serum VEGF level normalized and the monoclonal IgG-lamda, disappeared. The patient gradually recovered from a bedridden state and at the time of writing has no impairment in his activities of daily life. After the autoPBSCT, monoclonal IgG-kappa, protein was detected transiently in serum. The new monoclonal immunoglobulin was considered to be due to normal immune reconstitution after myeloablation rather than alteration of the abnormal plasma cell clone, similarly as oligoclonal immunoglobulins occur in multiple myeloma after autoPBSCT. AutoPBSCT with high-dose chemotherapy should be considered among the treatments of choice for POEMS syndrome.