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

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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

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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

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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