Sindrome di Sindrome di POEMSPOEMSOrvieto, 20-22 Novembre 2009
Rita EmiliRita EmiliS.C. Oncoematologia, A.O. S. Maria, S.C. Oncoematologia, A.O. S. Maria, TerniTerniUniversità degli Studi di PerugiaUniversità degli Studi di Perugia
DefinizioneDefinizione• PPolyneuropathyolyneuropathy
• OOrganomegalyrganomegaly
• EEndocrinopatyndocrinopaty
• MMonoclonalonoclonal plasma cell disorderplasma cell disorder
• SSkinkin changeschanges
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
EpidemiologiaEpidemiologia
• Età media : Età media : 50/60 anni50/60 anni
• Popolazione colpita : Popolazione colpita : Giapponesi, Europei, Giapponesi, Europei, Africani, Ispanici, Africani, Ispanici, AsiaticiAsiatici
Dispenzieri, Orphanet Enc., 2005Dispenzieri, Orphanet Enc., 2005
PatogenesiPatogenesi
RK Gherardi, Blood, 1994RK Gherardi, Blood, 1994
•CAUSE CAUSE ::
Aumento del livello delle citochine: Aumento del livello delle citochine: VEGF, IL-1β, TNF-α, IL-6 VEGF, IL-1β, TNF-α, IL-6
IL-1β in POEMS syndromeIL-1β in POEMS syndrome
RK Gherardi, Blood, 1994RK Gherardi, Blood, 1994
(D) In the other studied patient, radiolabeledI L-1p (D) In the other studied patient, radiolabeledI L-1p mRNA-producing cellsw ere similarly distributed in mRNA-producing cellsw ere similarly distributed in the interfollicular spacesthe interfollicular spaces
(A) Angiofollicular lymph node hyperplasia with (A) Angiofollicular lymph node hyperplasia with atrophic germinal centers (arrowheads) and sinusal atrophic germinal centers (arrowheads) and sinusal histicytosis (stars)histicytosis (stars)
(B) In situ hybridization performed with IL-p sense (B) In situ hybridization performed with IL-p sense probe used as control showing no signal probe used as control showing no signal
(C) In situ hybridization performed with IL-p anti-sense (C) In situ hybridization performed with IL-p anti-sense probe showing abundant radiolabeledI L-1p mRNA-probe showing abundant radiolabeledI L-1p mRNA-producing cells scatteredin the interfollicular spaces producing cells scatteredin the interfollicular spaces
Criteri di diagnosi Criteri di diagnosi
• Major criteria (both)Major criteria (both)
PolyneuropathyPolyneuropathy Monoclonal plasma cell-proliferative Monoclonal plasma cell-proliferative
disorderdisorder
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Criteri di diagnosiCriteri di diagnosi
• Minor criteria (plus at least one)Minor criteria (plus at least one)
Organomegaly Organomegaly Edema Edema Endocrinopathy Endocrinopathy Skin changes Skin changes Sclerotic bone lesionsSclerotic bone lesionsPapilledemaPapilledemaCastleman diseaseCastleman disease
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Criteri di diagnosi Criteri di diagnosi
• Known associationsKnown associations
Weight lossWeight loss ThrombocytosisThrombocytosis PolycythemiaPolycythemia HyperhidrosisHyperhidrosis ClubbingClubbing
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Criteri di diagnosiCriteri di diagnosi
• Possible associationsPossible associations
Restrictive lung diseaseRestrictive lung disease Thrombotic diathesesThrombotic diatheses ArthralgiasArthralgias Cardiomyopathy (systolic dysfunction)Cardiomyopathy (systolic dysfunction) FeverFever Low vitamin B12 valuesLow vitamin B12 values DiarrheaDiarrhea Pulmonary hypertensionPulmonary hypertension
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Caratteristiche cliniche alla diagnosiCaratteristiche cliniche alla diagnosi
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003Clinical features present at diagnosis in 99 patients with Clinical features present at diagnosis in 99 patients with POEMS seen at the Mayo Clinic from 1975 to 1998POEMS seen at the Mayo Clinic from 1975 to 1998
Caratteristiche cliniche alla diagnosiCaratteristiche cliniche alla diagnosi
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
POEMS patients – three seriesMayo
% n=99
French
% n=25
Japanese
% n =102
PPeripheral neuropathyeripheral neuropathy 100 100 100
OOrganomegalyrganomegaly 46 Ns Ns
EEndocrinopathyndocrinopathy 71 Ns Ns
MMonoclonal plasma cell dyscrasiaonoclonal plasma cell dyscrasia 100 100 75
SSkin Changeskin Changes 68 Ns Ns
Sclerotic bone lesionsSclerotic bone lesions 97 68 54
PapilledemaPapilledema 29 40 55
Extravascular volume overload Extravascular volume overload 39 Ns Ns
Castleman disease Castleman disease 11 24 19
Other featuresOther features
ThrombocytosisThrombocytosis 58 88 Ns
PolycythemiaPolycythemia 18 12 19
ClubbingClubbing 5 32 49
Ns – not statedNs – not stated
Polyneuropathy Polyneuropathy • Cerebrospinal fluid protein more than 50 Cerebrospinal fluid protein more than 50
mg/dltmg/dlt
• Peripheral neuropathy:Peripheral neuropathy: Distal, symmetric, progressiveDistal, symmetric, progressive
paresthesias paresthesias coolness coolness tingling tingling
• Motor involvement follows the sensory Motor involvement follows the sensory syntoms. syntoms.
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Organomegaly Organomegaly
• HepatomegalyHepatomegaly
• SplenomegalySplenomegaly
• LymphadenopatyLymphadenopaty (between 11%-(between 11%-30% Castelman disease presents)30% Castelman disease presents)
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
EndocrinopathyEndocrinopathy
• Diabetes mellitusDiabetes mellitus
• HypothyroidismHypothyroidism
• HyperparathyroidismHyperparathyroidism
• Gonadal axis abnormalityGonadal axis abnormality
• Adrenal axis abnormalityAdrenal axis abnormality
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Monoclonal plasma proliferative Monoclonal plasma proliferative disorderdisorder
• Serum M-spike (gm/dL) : Serum M-spike (gm/dL) : usually < 2usually < 2
• Monoclonal heavy chain : Monoclonal heavy chain : IgG > IgA > IgMIgG > IgA > IgM
• Monoclonal light chain : Monoclonal light chain : Lambda > 95%Lambda > 95%
• BM plasma cells % : BM plasma cells % : usually < 5usually < 5
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Skin changesSkin changes
• Hyperpigmentation Hyperpigmentation
• Acrocyanosis and plethoraAcrocyanosis and plethora
• Hemangioma/telangectasiaHemangioma/telangectasia
• HypetrichosisHypetrichosis
• ThickeningThickening
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Other features 1Other features 1• Sclerotic bones lesionsSclerotic bones lesions
mixed sclerotic and lytic mixed sclerotic and lytic osteosclerotic only osteosclerotic only lytic only lytic only > 1 lesion> 1 lesion
• Extravascular volume overloadExtravascular volume overload Peripheral edema Peripheral edema Ascites Ascites Pleural effusionPleural effusion
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Other features 2Other features 2
• PapilledemaPapilledema
• TrombocytosisTrombocytosis
• PolycythemiaPolycythemia
• ClubbingClubbing
• Weight loss more 10 poundsWeight loss more 10 pounds
• Fatigue Fatigue
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Overall survivalOverall survival
Dispenzieri, Hematology, 2005Dispenzieri, Hematology, 2005
A. Overall survival in 99 patients A. Overall survival in 99 patients receiving conventional dose receiving conventional dose chemotherapy.chemotherapy.
B. After peripheral blood stem cell B. After peripheral blood stem cell transplanttransplant.
Overall survivalOverall survival
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
TrattamentoTrattamento
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
TrattamentoTrattamento
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
• Radioterapia : Radioterapia : singole o multiple lesioni singole o multiple lesioni osteosclerotiche in una limitata areaosteosclerotiche in una limitata area
TrattamentoTrattamento
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
• Terapia sistemica : Terapia sistemica : diffuse lesioni diffuse lesioni osteoscleroticheosteoscleroticheAgenti alchilantiAgenti alchilantiCorticosteroidiCorticosteroidiChemioterapia ad alte dosi con trapianto di Chemioterapia ad alte dosi con trapianto di cellule staminalicellule staminaliTalidomideTalidomideLenalidomideLenalidomideBortezomibBortezomib
TrattamentoTrattamento
• TalidomideTalidomide
• LenalidomideLenalidomide
• BortezomibBortezomib
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
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TrattamentoTrattamento
• Talidomide: Talidomide: 200mg/die-300mg/die200mg/die-300mg/dieAnti VEGFAnti VEGFAnti TNFAnti TNF ImmunomodulatoreImmunomodulatore
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
TrattamentoTrattamento
• Lenalidomide: 15-25 Lenalidomide: 15-25 mg/die x 21 giorni mg/die x 21 giorni
(in associazione a desametasone)(in associazione a desametasone) Anti VEGFAnti VEGF Anti TNFAnti TNF ImmunomodulatoreImmunomodulatore
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
TrattamentoTrattamento
• Bortezomib: 1,3-1,6 Bortezomib: 1,3-1,6 mg/mqmg/mq Inibitore del proteosomaInibitore del proteosoma Inibitore di citochine Inibitore di citochine
proinfiammatorie e proinfiammatorie e proangiogenicheproangiogeniche
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
High -dose chemotherapy with High -dose chemotherapy with hematopoietic stem cell hematopoietic stem cell
transplantation 1transplantation 1
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
High -dose chemotherapy with High -dose chemotherapy with hematopoietic stem cell hematopoietic stem cell
transplantation 2transplantation 2
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
ConclusioniConclusioni• Diagnosi – Diagnosi – presenza di due criteri presenza di due criteri
maggiori e almeno uno minoremaggiori e almeno uno minore
• Diagnosi differenziale – Diagnosi differenziale – mieloma mieloma multiplo, malattia di Waldenström, multiplo, malattia di Waldenström, crioglobulinemia, amiloidosi primariacrioglobulinemia, amiloidosi primaria
• Terapia –Terapia – radioterapia e chemioterapia radioterapia e chemioterapia
• Sopravvivenza – Sopravvivenza – migliore rispetto ai migliore rispetto ai pazienti con mieloma multiplo.pazienti con mieloma multiplo.
Dispenzieri, Blood, 2003Dispenzieri, Blood, 2003
Grazie per l’attenzioneGrazie per l’attenzione