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

Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem-cell transplantation
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  Efficacy of lenalidomide plus dexamethasone for POEMSsyndrome relapsed after autologous peripheral stem-celltransplantation Barbara Vannata, 1 Luca Laurenti, 1 * Patrizia Chiusolo, 1 Federica Sora`, 1 Mario Balducci, 2 Mario Sabatelli, 3 Marco Luigetti, 3 Claudia Giannotta, 4 Valerio De Stefano, 1 Giuseppe Leone, 1 and Simona Sica 1 POEMS syndrome is a rare paraneoplastic condition associated to anunderlying plasmacellular dyscrasia. The pathogenesis of POEMS ispoorly understood, but overproduction of VEGF, probably secreted byclonal plasma cells, is thought to be responsible for the signs andsymptoms of the syndrome, and it seems to be useful for the monitor-ing of the response to therapy. At present, an effective therapeuticoption for the patients is represented by autologous peripheral bloodstem-cell transplantation (aPBSCT), although relapses have beendescribed, and there is an important morbidity associated with thisprocedure. Before the implementation of aPBSCT, the clinical courseof POEMS syndrome was characterized by progressive polyneuropathypotentially leading to death for respiratory failure. Given the highserum and plasma levels of VEGF observed in POEMS patients, theuse of antiangiogenetic drugs such as thalidomide and lenalidomideand other drugs with anti-VEGF and anti-TNF effect such as bortezo-mib have been considered to treat this syndrome. There are evidencesof lenalidomide benefit in both front-line and previously treatedpatients, but scanty data are available about its use for relapse afteraPBSCT. Here, we report the successful use of lenalidomide in apatient who relapsed after aPBSCT. POEMS is the acronym referring to the main features of the syndrome: pol-yradicoloneuropathy, organomegaly, endocrinopathy, monoclonal plasma-celldisorder, and skin changes [1–4]. There are also other typical findings of thissyndrome including papilledema, extravascular overload, sclerotic bonelesions, thrombocytyosis/erythrocytosis and elevated VEGF levels, thromboticdiathesis, and abnormal lung function tests, not comprised in the acronym ordiagnostic criteria, but with known prognostic value [4,5]. First-line therapy forpatients affected by POEMS syndrome is not well established. Nowadays, forfit patients, the use of alkylating agent and aPBSCT seems to be the beststrategy in POEMS [6–13]. For unfit patients, in which the high-dose therapyis not recommended, many therapeutic approaches have been suggested:steroids, low-dose alkylators associated with steroids, radiotherapy. Moreover,new agents were recently investigated including thalidomide, lenalidomide,bortezomib [14,15], and bevacizumab [16–18]. Lenalidomide, an immunomo-dulatory drug with a mechanism of action comprising both tumoricidal andimmunomodulatory effects has been tested with good results in untreated andpretreated POEMS patients [19–22]. Lenalidomide is generally preferred tothalidomide and bortezomib because of their significant neurological toxicity.Its use is based on the assumption that POEMS is a cytokine-mediated syn-drome. VEGF appears to be the main cytokine in this disorder. It is an endo-thelial mitogen and an angiogenic factor, which increases vascular permeabil-ity. Other cytokines include tumor necrosis factor-alpha (TNF- a ), interferongamma (IFN  g ), interleukin-1 b  (IL-1 b ), and interleukin-6 (IL-6). IL-1  b  and IL-6are both able to stimulate the VEGF production [23].In multiple myeloma (MM), the association of lenalidomide and dexame-thasone showed efficacy even in patients with IgA M-protein, with poor per-formance status, in the presence of neuropathy and also for patients previ-ously receiving aPBSCT [24]Here, we describe a case of a 52-year-old man admitted to our depart-ment on 2003. He was diagnosed with symmetrical peripheral sensorimotorpolyneuropathy: he presented with muscle weakness with stepwise progres-sion to tetraplegia accompanied by loss of weight and pain to the extrem-ities. EMG showed an axonal and demyelinating polyneuropathy moresevere in lower limbs. At the moment of admission, the laboratory tests dis-played the presence of IgA l  monoclonal gammopathy, normochromic nor-mocytic anemia, hypothiroidism. Bone-marrow fine-needle aspiration showednormal plasma-cell count. On physical examination, he also showed spleno-megaly, hyperpigmantation, and sclerodermic changes of the skin, and theX-ray of the bone pointed out the presence of several lytic lesions of thespine and ribs and a wide osteosclerotic lesion of the left homerus withextention to the surrounding soft tissues. He started therapy with predniso-lone and cyclophosphamide followed by peripheral stem-cell harvest andautologous stem-cell transplantation after Melphalan 200 mg/m 2 as condi-tioning regimen on April 2004 [6]. After transplant, complementary radiother-apy to the left homerus was administered. He obtained a hematologic partialremission [25–27], with the persistence of serum M-protein detected byimmunofixation and a consistent improvement of the neuropathy with abilityto walk and disappearance of pain. Then, he was followed for 6 years asoutpatient, maintaining a hematologic partial response until June 2010.At that time, the patient was admitted to the hospital for anasarca, dyspneaand orthopnea, weight loss, weakness, and recurrence of pain to the lowerlimbs (ECOG performance status 4, ADL index 2/6). He was unable to walk.He also showed further pelvic, vertebral and femoral lesions, hyperpigmenta-tion, and sclerodermic changes of the skin with fingernail clubbing. PlasmaVEGF level at relapse was 1,629 pg/ml (normal range, 0–1,000 pg/ml).Because of his poor performance status, high-dose chemotherapy was not afeasible option: we started lenalidomide/dexamethasone (lenalidomide 25 mgdays 1–21 and dexamethasone 40 mg once weekly). After first cycle, thepatient showed a sudden improvement of fluid overload with resolution ofascites and dyspnea, but persistence of skin hyperpigmentation and no changeof neurological symptoms. Nevertheless, we were able to discharge him aftersecond cycle of therapy. After four cycles, he obtained a significant responsewith disappearance of splenomegaly and a slight improvement of the skinmelanosis, while immunofixation showed the persistence of monoclonal com-ponent IgA l . We observed the disappearance of M-protein after six courses oflenalidomide and plasma VEGF dosage done after the eighth Len–Dex cyclewas normal as well as thyroid function. Also, neurological impairment improvedgradually. After the sixth cycle, the patient was able to walk with bilateral sup-port, and after the 10th cycle, he could walk independently (Table I).PET–CT scan showed the presence and persistence of increased FDGuptake to the bone lesions with SUV max of 11.6 to the left femur. After his10th cycle, radiotherapy was administered to both his femora, to the pelvis, andto the T10 bone lesion (30 Gy) based on FDG uptake on FDG–PET/CT scan.At this point, he was able to walk easily, and his ADL index was 4/6. Threemonths after radiotherapy, lenalidomide was reintroduced because of reappear-ance of high plasma VEGF levels (2,574 pg/ml) even if no further manifesta-tions of the disease were detected with a follow-up of 19 months after relapse.Lenalidomide was the only feasible therapeutic option for our relapsedPOEMS patient, unfit for chemotherapy-based regimens. The response tolenalidomide was prompt and progressive, allowing a marked improvementof functional scales. Some reports suggest efficacy of lenalidomide inPOEMS syndrome both in untreated patient unsuitable for high-dose chemo-therapy and in relapsed patients as salvage therapy [19–21].The advantage of lenalidomide in POEMS patients could be the doublenature of tumoricidal and antiangiogenic effects with ability to affect both cyto-kine production and plasmacellular disorder. After six lenalidomide cycles, ourpatient achieved a hematologic PR with persistence of monoclonal IgA byimmunofixation, and normal VEGF level after eight cycles. We stopped lenali-domide in order to treat persistently PET-active bone lesions with radiotherapy.Three months after radiotherapy, we resumed lenalidomide at the dose of25 mg per day on the basis of increasing VEGF levels. This data confirmsthe opportunity to continue lenalidomide as maintenance until relapse or tox-icity as in MM. After 10 months, lenalidomide showed a low-toxicity profilewithout dose reduction or delay. letters  American Journal of Hematology  641  We do not know the duration of response after transplant in POEMS, butrelapses are described. Lenalidomide could be a good therapeutic option asconsolidation-maintenance after transplant in responding patients, also con-sidering data showing a significant prolongation of progression–free survivalwith lenalidomide maintenance after aPBSCT in MM pts [28–30].Based on our experience, the use of lenalidomide plus dexamethasoneseems to be the best choice for unfit POEMS patients relapsing afteraPBSCT. Its use should be continued till relapse or toxicity, monitoringVEGF levels. 1 Department of Hematology, Catholic University of the Sacred Heart, Rome, Italy;  2  Department of Radiotherapy, Catholic University of the Sacred Heart, Rome,Italy;   3  Department of Neurology Catholic University of the Sacred Heart, Rome,Italy;   4  Department of Translational Medicine, Milan University, 2nd Neurology,IRCCS Humanitas Institute, Rozzano, Milan, Italy; *Correspondence to: Luca Laurenti, Department of Hematology, Catholic University Of Sacred Heart, Hospital ‘‘A. Gemelli,’’ Largo A. Gemelli 8. 00168,Rome, Italy Received for publication 2 January 2012; Accepted 2 March 2012 Conflict of interest: Nothing to report.Published online 12 March 2012 in Wiley Online Library ( 10.1002/ajh.23195  References 1. Bardwick PA, Zvaifler NJ, Gill GN, et al. Plasma cell dyscrasia with polyneur-opathy, organomegaly, endocrinopathy, M protein, and skin changes: ThePOEMS syndrome. Report on two cases and a review of the literature. Medi-cine 1980;59:311–322.2. Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: A studyof 102 cases in Japan. Neurology 1984;34:712–720.3. Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: Definitions andlong-term outcome. Blood 2003;101:2496–2506.4. Dispenzieri A. POEMS syndrome: 2011 update on diagnosis, risk-stratificationand management. Am J Haematol 2011;86:591–601.5. Allam JS, Kennedy CC, Aksamit TR, Dispenzieri A. Pulmonary manifestationin patients with POEMS syndrome. A retrospective review of 137 patients.Chest 2008:133:969–974.6. Laurenti L, De Matteis S, Sabatelli M, et al. Early diagnosis followed by front-line autologous peripheral blood stem cell transplantation for patients affectedby POEMS syndrome. Leuk Res 2008;32:1309–1312.7. Gupta S, Rana V, Chandra D, et al. Autologous peripheral stem cell transplantfor POEMS syndrome: A case report. Hematology 2006;11:361–363.8. 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Definition of organ involvement andtreatment response in immunoglobulin light chain amyloidosis (AL): A consen-sus opinion from the 10th International Symposium on Amyloid and Amyloido-sis, Tours, France, April 18–22, 2004. Am J Hematol 2005;79:319–328.27. Merkies IS, Schmitz PI, van der Meche´ FG, Samijn JP, van Doorn PA; Inflam-matory Neuropathy Cause and Treatment (INCAT) group. Clinimetric evalua-tion of a new overall disability scale in immune mediated polyneuropathies. JNeurol Neurosurg Psychiatry 2002;72:596–601.28. Palumbo A, Gay F, Falco P, et al. Bortezomib as induction before autologoustransplantation, followed by lenalidomide as consolidation-maintenance inuntreated multiple myeloma patients. J Clin Oncol 2010;28:800–807.29. Mc Carthy PL, Owzar K, Anderson KC et al. Phase III intergroup study oflenalidomide versus placebo maintenance therapy following single autologousstem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. JClin Oncol 28:15s, 2010 (suppl; abstr 8017).30. Attal M, Cristini C, Marit G, et al. Lenalidomide maintenance after transplanta-tion in Multiple Myeloma. J Clin Oncol 28:15s, 2010 (suppl; abstr 8018). TABLE I. Patient Characteristics Before and After Len–Dex Therapy Diagnosis of POEMS  (2003)1 year afteraPBSCT (2005) R elapse( J une 2010) A fter 6 cyclesof lenalidomide A fter 10 cyclesof lenalidomide P erformance status ( ECOG ) 2 0 4 3 2 H yperpigmentation Present Resolved Present Improved Improved E xtravascular overload Absent Absent Present Resolved Resolved I NCAT disability scale A rm disability 5 0 4 1 0 L eg disabilitiy 7 2 6 4 2 T otal [26] 12 2 10 5 2 S plenomegaly Present Resolved Present Resolved Resolved B one marrow plasma cells 0.5 0 2 2 n.a. M -protein IgA l  byimmunofixationIgA l  byimmunofixationIgA l  byimmunofixationNegative byimmunofixationIgA l  byimmunofixation IGA a (mg/dl) 764 406 566 499 541 TSH a 6.24 n.a. 6.23 2.24 1.5 FT 4 a 10 n.a. 8.6 11.2 10.6 VEGF a (pg/ml) n.a. n.a. 1629 n.a. 962 ADL  index n.a. n.a. 2/6 4/6 4/6 a Normal values: VEGF 0–1000 pg/ml; TSH 0.35–2.80  m UI/ml; FT4 8.5–15.5 pg/ml; IgA 70–400 mg/dl.INCAT disability sum score  5  arm disability scale (range 0–5); leg disability scale (range 0–7) [26].INCATrange: 0 (no signs of disability) to 12 (maximum disability) [26]. letters 642  American Journal of Hematology
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