GAMAPATAS MONOCLONALESDivisin HematologaHospital de Clnicas Jos de San Martn

MACROGLOBULINEMIADE WALDENSTRM

GAMAPATA MONOCLONAL Ig MENTIDADES CLNICAS M.G.U.S.: Ig. M < 3 gr/dl. M.O.: sin infiltracin Asintomtica

Desrdenes relacionados con la Ig.M: Neuropatas (sntomas por Ig.M Crioglobulinas M.O. no infiltrada) Crioaglutininas Amiloidosis

Macroglobulinemia de Waldestrm: Ig.M M.O. infiltrada Asintomtica Sintomtica

MACROGLOBULINEMIA DE WALDENSTRMDEFINICINDesorden linfoproliferativo poco comn,caracterizado por una infiltracin de mdula seapor linfocitos de aspecto maduro y / o linfoplasmocitos y plasmocitos y una gamapata monoclonal Ig M.

A.P. (W.H.O.): Linfoma linfoplasmoctico

Definicin clnicopatolgicade la MWDiagnstico histopatolgico de Linfoma Linfoplasmoctico usando el criterio de la REAL/WHO

Presencia de una proteina monoclonal Ig. M, sin importar su concentracinOwen RG, et al. Semin Oncol. 2003;30:110-115.

Falta de relacin entre el nivel de Ig. M y el compromiso de la M.O.BM Involvement0200040006000800010,00012,00014,0000%20%40%60%80%100%Treon SP, Blood. 2009;114:2375-2385.

MACROGLOBULINEMIA DE WALDENSTRMCARACTERISTICAS BAJA FRECUENCIA :

6% de todas las gamapatas monoclonales 2 a 5 casos / milln de habitantes / ao

EDAD AVANZADA :

Media : 71 aos Hombre / mujer : 2:1

HISTORIA NATURAL :

Enfermedad indolente 1/3 mueren por otras causas (no por W.M.)

MACROGLOBULINEMIA DE WALDENSTRMETIOLOGA Casos familiares : asociados a otros sindromes linfoproliferativos con o sin gamapata monoclonal

Estimulacin antignica crnica : Hepatitis C H.I.V Otras enfermedades autoinmunes

MACROGLOBULINEMIA DE WALDENSTRM

Biopsia de Mdula sea: muy importante Infiltracin por linfocitos de aspecto maduro,plasmocitos y linfoplasmocitos.

Fenotipo: CD 19 + FMC 7 + CD 20 +++ CD 11c neg. CD 24 + CD 5 neg. CD 25 + CD 10 neg. Citogentica: del 6 q

MACROGLOBULINEMIA DE WALDENSTRMClasificacin clnica ASINTOMTICA : supervivencia a poblacin general

SINTOMTICA : supervivencia 5 aos ms corta que poblacin general

MACROGLOBULINEMIA DE WALDENSTRMCUADRO CLNICO Motivo de consulta:

Astenia progresiva Anemia (38%) Hiperviscosidad (31%) Adenopatas (25%) Sntomas B (23%) Sangrado (23%) Sntomas neurolgicos (22%) Caractersticas clnicas:

Sntomas debidos al crecimiento tumoral Sntomas debidos a la paraproteina

MACROGLOBULINEMIA DE WALDENSTRMCUADRO CLNICOINFILTRACION TUMORALMdula seaGanglios Bazo M.W. Ig. M CIRCULANTEHiperviscosidadCrioglobulinas Crioaglutininas Ig. M TISULARNeuropata Depsito en glomrulo renal (Sindrome nefrtico)Amiloidosis

MACROGLOBULINEMIA DE WALDENSTRMCUADRO CLNICO Infiltracin tumoral

Mdula sea anemia leucopenia plaquetopenia

Ganglios linfticos Adenopatas (15 a 25%)

Bazo Esplenomegalia (15%)

Otros rganos

MACROGLOBULINEMIA DE WALDENSTRMCUADRO CLNICO Hiperviscosidad

CefaleasConfusin mentalAlteraciones de la visinEpistaxisHipertensin arterialInsuficiencia cardacaComa

Fondo de ojo de un paciente con hipervicosidadReproduced with permission from Dr. Marvin Stone.

Fondo de ojo de pacientes conhipervicosidad Graphic reproduced with permission.

MACROGLOBULINEMIA DE WALDENSTRMCUADRO CLNICO Crioglobulinas obstruccin de pequeos vasos en zonas expuestas al fro (10%)

Crioaglutininas anemia hemoltica por anticuerpos fros (5%)

Paciente con crioglobulinemiaPre-PheresisPost-PheresisGraphic used with permission.

MACROGLOBULINEMIA DE WALDENSTRMCUADRO CLNICO Neuropata

22% de los pacientes

La Ig. M acta como anticuerpo contra la mielina

(MAG glicoproteina anti mielina)

Polineuropata desmielinizante

Se benefician con tratamiento precoz con Rituximab

MACROGLOBULINEMIA DE WALDENSTRMTRATAMIENTO Cuando?

Cmo?:

MACROGLOBULINEMIA DE WALDENSTRMClasificacin clnica ASINTOMTICA : supervivencia a poblacin general

SINTOMTICA : supervivencia 5 aos ms corta que poblacin general

Panel de consenso para iniciartratamientoHb 10 g/dL por la infiltracinPLT < 100,000/mm3 por infiltracinHiperviscosidad sintomtica (> 4.0 cp)Neuropata moderada a severaCrioglobulinemia sintomtica, crioaglutinina sintomtica, amiloidosis, u otro evento relacionado con la enfermedadKyle RA, et al. Semin Oncol. 2003;30:116-120.

MACROGLOBULINEMIA DE WALDENSTRMTRATAMIENTO

Cmo?: Plasmafresis Rituximab (anti CD 20) Rituximab + Ciclofosfamida + DXM Clorambucil Bendamustine Talidomida o Lenalidomida Bortezomid Cladribine TAMO ( slo Jvenes )

Alotrasplante (slo en ptes jvenes y dentro de un ensayo clnico)

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicos

Caso n 1:

Paciente de sexo femenino,82 aos.

Consulta por primera vez en el ao 2000 por un

Proteinograma:leve hiperproteinemia ; componente M en gama rpidaIg M de baja concentracin

Proteinuria fisiolgica

Mdula sea: normal, sin infiltracin

Fondo de ojo normal

.

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicos

Caso n 1:

2005 Asintomtica , pero Ig M a 2,5 gr/l

M.O. 25 % de infiltracin

2009 Fractura traumtica de pelvis y costillas

2010 Fractura traumtica de cuello de fmur.

2011 Leve anemia.Hematomas espontneos. Componente M 3,5 gr/l

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2:

Paciente de 48 aos de sexo masculino

Marzo de 2011: consulta por episodios de diarrea asociados a dolor lumbar y prdida de 14 kg. de peso en un ao Lab.: discreta anemia (hto 36 %) Eritro 93 Funcin renal normal LDH normal 2 microglobulina Serologas virales negativas

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2:

Julio 2011: continua con diarreas , dolor lumbar y se agregan edemas generalizados.

> deterioro del estado general se interna Anemia,Eritro ,> hipoalbuminemia

2 microglobulina 17

No adenomegalias ni visceromegalia

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2: Mdula Osea :

PAMO y Biopsia:celularidad 25 % de infiltracin por linfocitos, linfoplasmocitos y plasmocitos.Las clulas linfticas son: CD 19 ++ CD 20 ++ CD 38 ++ las clulas plasmticas son CD 138 ++ cadenas +

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2: Paciente con

Componente monoclonal Ig. M

Mdula sea infiltrada por linfoplasmoctos

Diagnstico: Macroglobulinemia de Waldenstrm

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2: Inici tratamiento con :Rituximab + Ciclofosfamida + Dexametasona

Ciclos cada 21 das

Cumpli 2 ciclos.Buena respuesta al tratamiento con mejora

del dolor,de las diarreas, disminucin de los edemas y de la

hipoalbuminemia

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2:

Diarreas? Sindrome de mala absorcin

Linfoma? Amilodosis? Otra causa?

VCC negativa EGC mucosa duodenal y yeyuno alteradasAtrofia de las vellosidades,no infiltracin por linfocitos patolgicos,no linfangiectasias. No amiloide.

Se descart enfermedad celaca

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2:

Lumbalgia ?

Rx neg

RNM de columna : no lesiones osteolticas espondiloartrosis moderada alteracin de la seal de la mdula sea

MACROGLOBULINEMIA DE WALDENSTRMCasos clnicosCaso n 2:

Proteinograma : P.T. 7,8 gr /l Albmina 2,8 glob. 3,34 comp M 2,35 Ig.M 2500 Ig A 155 Ig.G 1162 Proteinuria : 0,65 gr/ 24 hs Bence Jones + cadenas lambda

AMILOIDOSIS

AMILOIDOSIS Desorden poco frecuente que se produce por el depsito de protena amiloide en los tejidos

La protena amiloide se caracteriza por su configuracin tridimensional como estructura plegada

Es resistente a la protelisis y tiene afinidad por el rojo congo

AMILOIDOSIS

AMILOIDOSIS PRIMARIA Es una neoplasia de clulas plasmticas que segregan una inmunoglobulina anormal, (cadena liviana) que se deposita en varios rganos en forma de estructura plegada y causa la disfuncin de los mismos

Incidencia anual: 8 casos / 1.000.000 de habitantes

Edad media: 55 aos

Predominio 2:1

AMILOIDOSIS PRIMARIACuadro clnico Fatiga dificultad para subir escaleras

Macroglosia 10%

Prpura (periorbital) 15%

Depsitos periarticulares y en estructuras submandibulares

Sndrome del tnel carpiano (25%)

Hipoesplenia

Amiloidomas

AMILOIDOSIS PRIMARIAEcocardiograma: Engrosamiento de las paredes y vlvulas Engrosamiento del septum interventricular Birrefringencia caracterstica Textura granular

AMILOIDOSIS PRIMARIARiones: Biopsia renal: depsitos en mesangio y membrana basal. El grado de proteinuria no se correlaciona con el deposito de amiloide

Rion Normal vs Amiloidoisis

Amiloidosis Renal

Luz Polarizada - Birrefringencia

AMILOIDOSIS PRIMARIA

AMILOIDOSIS PRIMARIA

AMILOIDOSIS PRIMARIA

AMILOIDOSIS PRIMARIAEstudios complementarios Componente monoclonal en sueroProteinograma50%Inmunofijacin90%IgG33%Cadenas Livianas 25% (80%)IgA10%

Cadenas livianas libres

Proteinuria en rango nefrtico 30% Cadenas livianas en orina 75%

Fosfatasa alcalina 25%

Dficit de factor x 10%

Trombocitosis 5-10%

AMILOIDOSIS PRIMARIAEstudios complementarios Estudio de la mdula sea clulas plasmticas < 10%

Depsito amiloide (tincin Rojo Congo)Grasa subcutnea 80%Mucosa rectal70%Mdula sea55%Biopsia del rgano afectado

Ecocardiograma

BIOPSIA DE MDULA SEATincin con rojo Congo

AMILOIDOSIS PRIMARIADiagnstico De sospecha: sindrome caracterstico + componente monoclonal srico y/o urinario

Definitivo: depsito de sustancia amiloide tipo AL en la biopsia de un tejido u rgano afectado.

PRONOSTICO Y EVOLUCION

ALGORITMO DIAGNOSTICOManifestacin clnica sugestivaBiopsia grasa subcutnea(tincin de Rojo Congo)Proteinograma e IF srica + urinariaMielogramaComponente monoclonalDepsito cadena ligera IgALBiopsia MOBiopsia rectalBiopsia rgano afectoFamiliarSecundariaSenil++Si (-)Si (-)

AMILOIDOSIS PRIMARIATRATAMIENTO Melfaln Dexametasona

Melfaln Dexametasona Talidomida

Ciclofosfamida Dexametasona Talidomida

Bortezomid - Dexametasona

TAMO Alternativa prometedora en pacientes < de 70 aos con solo uno o dos rganos afectados Respuestas hematolgicas y de rganos pero Gran morbimortalidad relacionada con el trasplante Tasa de mortalidad por el trasplante: 25 al 30%

Caso ClnicoPaciente de 39 aos, sin antecedentes clnicos relevantes

Inicia su enfermedad hace aproximadamente 4-5 meses con edemas progresivos de Miembro Inferiores

Evaluada por nefrologa donde se constata Sndrome Nefrtico con Proteinuria Inicial de 10.2g/24hs

Biopsia Renal Cilindro crtico medular que contiene hasta 15 glomrulos por corte, los mismos se hallan difusamente alterados por el deposito de un material acidfilo homogneo en el mesangio y paredes capilares (subendotelial y subepitelial). Positivos con el Rojo Congo y Tioflavina T. Tbulos con atrofia (1%). Intersticio con fibrosis leve. En la muestra se incluye un segmento de pared arterial con leve fibrosis intimal. Algunas arteriolas presentan hipertrofia muscular y otros escasos depsitos de amiloide segmentarios. Inmunofluorescencia IgG, IgA, IgM, C1q, C3 y Fibringeno: Negativos. Cadenas Lambda Positivas en mesangio glomerular. Inmunohistoquimica. Protena Amiloide A. negativa.

Dco de Amiloidosis Renal Clase IV (deposito difuso mesangiocapilar).

Examen Fsico se encuentra en regular estado gral, debilidad generalizada, con edemas de MMII,

no impresiona hepatoesplenomegalia, no prpura ni signos de equimosis en piel, no impronta de lengua, como as tampoco hipotensin postural, no signos de disautonomia,

si refiere parestesias en extremidades a predominio de manos, tambin refiere alteraciones en el ritmo evacuatorios con periodos de constipacin que alteran con episodios de diarrea.

EstudiosHto 38.7 hb 13.2, plaq 232.000, Gb 7.940 (69/21/7/1/0), VSG 50 TGP/O 14/17 FAL 136 (normal) Creat 0.6, urea 29, Clearance de Creat 148.7 ml/min, calcio 7.7, Fosfatemia 4.2. Coagulograma normal. TP 40% Kptt 30. Proteinograma Electrofortico:P:T: 4.1/Alb.:2.12 /0.17 /0.78 /0.48 /0.55 de Gamma. Inmunofijacion Negativa. Uroproteinograma. 10.2 g/24hs de proteinuria glomerular de alta Selectividad. Bence Jones Negativa.

Ecocardiograma: Diametros del VI conservado, Funcin sistlica Normal AI y RAo Normal, septum normal, no signos de Derrame pericardico. Fraccin de acortamiento 44%. ECG Normal, en trazado y en la intensidad del Voltaje.Troponina T / I : Normal. BNP 758 (alterado > de 450)

Estudios II

Ecografa Abdominal: Hgado y bazo con dimetros conservados, homogneos.

EMG de 4 Miembros: Dentro de caractersticas normales (Velocidad de Conduccin Motora y Sensitiva Normal, P.U.M Normales, Fibrilaciones ausentes, patrn de Reclutamiento: interferencial).

Estudios IIIEstudio de Medula sea: CMF: 2% de clulas plasmticas Patolgicas Monoclonales cadena Lambda (citoplasmtica) Expresin fuete de CD38++, CD138++.

Anatoma Patologica: celularidad del 60% relacin M/E conservada, se identifica un 12% de clulas plasmticas siendo positivas para CD138 y cadena liviana Lambda. Se observa deposito de material amiloide (positivo con Rojo Congo y Tioflavina T/ luz polarizada) en tejido adventicial perivascular. Trama reticulinica Conservada. CTG 46 XX [15].Dco Plasmocitosis Monoclonal / Amiloidosis.

Estudios IVBiopsia de Grasa Subcutnea: Deposito de un material acidfilo homogneo, entre clulas grasas y en segmento de pared vascular, que muestra positividad con Rojo Congo y Tioflavina T.

Con Diagnostico de: AMILOIDOSIS PRIMARIA SISTEMICA TIPO AL.

TratamientoInicia Tratamiento con Protocolo CTD

(Ciclofosfamida 500 mg VO das 1-8-15, Talidomida 100mg/da continuo; Dexametasona 40 ciclos de 4 das 1-4 y 9-12)

EvolucinLuego de completar 2 ciclos de tratamiento intercurre con dos internaciones

1 con cuadro de disnea, se descarta TEP, completa tto ATB por Neumona, 20 das posteriores

2 nuevo episodio de astenia y disnea progresiva hasta CF IV- reposo- se constata derrame pleural bilateral con franco predominio derecho casi masivo, requiere drenaje con caractersticas de trasudado, se asume como probable etiologa por Insuficiencia cardiaca congestiva.

EvolucinDebido a esta intercurrencia se asume como progresin de enfermedad sistmica.

Realizando 5 ciclo de Bortezomib asociado Ciclofosfamida y dexametasona (CyBorD).En plan de reevaluacion general, con nuevo dosaje de BNP/ProBNP., Troponina T/I, Cadenas Livianas Libres.

EvolucionSe realiza Nueva Bp de Medula que evidencia dismunucion del componente amiloide.

Cadenas Livianas Libre: precipitacion muy debil Normalizacion de ProBNP

Se asume como buena Respuesta Parcial se encuentra en plan de Consolidar con TAMO

MUCHAS GRACIAS!

REAL/WHO, Revised European-American Lymphoma / World Health Organization.I mentioned early on that Waldenstrms macroglobulinemia is a lymphoma and best classified under the pathological diagnosis of lymphoplasmacytic lymphoma using either the REAL or WHO criteria. Roughly 95% of the lymphoplasmacytic lymphomas make IgM and therefore are Waldenstrms, but a small percentage5%can make either IgG or IgA, or are what we call nonsecretory.The reason why I included regardless of serum level has to do with the study that we published in the journal Blood in the How I Treat series 2 years ago where we looked at the relationship of IgM to bone marrow involvement. *What you can see here is that theres absolutely no relationship between IgM and bone marrow involvement. You can have patients who have very little disease involvement but who make a lot of IgM. Many times, we have to treat these patients because theyre symptomatic from hyperviscosity because their IgM level is very high. At the other extreme, you can have patients who have a lot of disease involvement of their bone marrow but make very little IgM. For this reason, theres no cutoff. Its important to recognize this because you can have 2 patients that have the same IgM level but have vastly different underlying disease burden.*In this slide, we see a funduscopic examination of a patient with Waldenstrms with hyperviscosity syndrome, and you can see the dilated retinal blood vessels. In fact, you can see this kind of sausage appearance to these retinal vessels because you have periodic smooth muscle apertures that control the blood flow and, if you distend them out, you can see that the retinal vessels actually look like sausages.

*The patients funduscopic examination of his retina showed extensive hemorrhages in the periphery along with dilated blood vessels, which are shown on the right. You can see in the center that the patient had a sizeable hemorrhage.*This is an individual whose IgM would precipitate in the extremities, under cold conditions, and block peripheral blood vessels. The patient would then develop acrocyanosis leading to the cyanotic appearance that you see here. This is an individual that we then heated and plasma pheresed. By removing the cryoglobulins, we were able to restore his perfusion.

*cp, centipoise.Not everybody that has Waldenstrms needs to be treated. If a patient has any of these factors, its fair game to treat based on consensus recommendations, but otherwise watch and wait is appropriate.**What you can see here is that theres absolutely no relationship between IgM and bone marrow involvement. You can have patients who have very little disease involvement but who make a lot of IgM. Many times, we have to treat these patients because theyre symptomatic from hyperviscosity because their IgM level is very high. At the other extreme, you can have patients who have a lot of disease involvement of their bone marrow but make very little IgM. For this reason, theres no cutoff. Its important to recognize this because you can have 2 patients that have the same IgM level but have vastly different underlying disease burden.******cp, centipoises; HA, hemagglutinin; HCT, hematocrit; PLT, platelet; Sxs, symptoms; WBC, white blood cell count.Even though this is a lymphoma, its very rare that you can actually see either adenopathy or splenomegaly, which only occur in about 15% of patients. Most of the disease is actually found in the bone marrow, and as a result, the patients can develop myelosuppression and require therapy. Very commonly, we have to treat patients, not because of the bulk of disease, but because of the IgM being produced; if you make too much IgM, it can lead to hyperviscosity syndrome. Roughly 90% of the IgM that we make is kept in the intravascular space because IgM is a big bulky molecule. If the IgM levels go up, it can trigger hyperviscosity levels to go up, resulting in nose bleeds, headaches, as well as impaired vision. You tend to see this happen when the patients IgM levels usually exceed either 5000-6000 mg/dL or 4 centipoise.Another way patients can get into trouble is because the IgM acts as an autoantibody. Most typically, it tends to either bind the myelin sheaths of nerves, causing their destruction and resulting in a peripheral sensory neuropathy. This can occur in about 20% to 22% of patients with Waldenstrms.You can also see patients develop cryoglobulins. This is when the IgM under cold conditions can precipitate and cause blocking of peripheral blood vessels, leading to acrocyanosis. Sometimes these patients also get peripheral ulcerations.Patients can develop cold agglutinins where, under cold conditions, the IgM can bind to red blood cells, causing their destruction. Weve even had patients who, looking at summer vs winter, can have up to a 10-percentage point difference in their hematocrit.cp, centipoises; HA, hemagglutinin; HCT, hematocrit; PLT, platelet; Sxs, symptoms; WBC, white blood cell count.Even though this is a lymphoma, its very rare that you can actually see either adenopathy or splenomegaly, which only occur in about 15% of patients. Most of the disease is actually found in the bone marrow, and as a result, the patients can develop myelosuppression and require therapy. Very commonly, we have to treat patients, not because of the bulk of disease, but because of the IgM being produced; if you make too much IgM, it can lead to hyperviscosity syndrome. Roughly 90% of the IgM that we make is kept in the intravascular space because IgM is a big bulky molecule. If the IgM levels go up, it can trigger hyperviscosity levels to go up, resulting in nose bleeds, headaches, as well as impaired vision. You tend to see this happen when the patients IgM levels usually exceed either 5000-6000 mg/dL or 4 centipoise.Another way patients can get into trouble is because the IgM acts as an autoantibody. Most typically, it tends to either bind the myelin sheaths of nerves, causing their destruction and resulting in a peripheral sensory neuropathy. This can occur in about 20% to 22% of patients with Waldenstrms.You can also see patients develop cryoglobulins. This is when the IgM under cold conditions can precipitate and cause blocking of peripheral blood vessels, leading to acrocyanosis. Sometimes these patients also get peripheral ulcerations.Patients can develop cold agglutinins where, under cold conditions, the IgM can bind to red blood cells, causing their destruction. Weve even had patients who, looking at summer vs winter, can have up to a 10-percentage point difference in their hematocrit.What you can see here is that theres absolutely no relationship between IgM and bone marrow involvement. You can have patients who have very little disease involvement but who make a lot of IgM. Many times, we have to treat these patients because theyre symptomatic from hyperviscosity because their IgM level is very high. At the other extreme, you can have patients who have a lot of disease involvement of their bone marrow but make very little IgM. For this reason, theres no cutoff. Its important to recognize this because you can have 2 patients that have the same IgM level but have vastly different underlying disease burden.*This slide shows an overview of the presentation. The introduction will discuss the epidemiology, clinical presentation, diagnosis, and staging of myeloma and the initial approaches to treatment, including current options and novel agents and combinations. There will be a brief discussion of autologous stem cell transplantation in patients with myeloma and how to care for patients who are not transplantation eligible.*In this slide, we see a funduscopic examination of a patient with Waldenstrms with hyperviscosity syndrome, and you can see the dilated retinal blood vessels. In fact, you can see this kind of sausage appearance to these retinal vessels because you have periodic smooth muscle apertures that control the blood flow and, if you distend them out, you can see that the retinal vessels actually look like sausages.

*