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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome Tapan Kadia, M.D. Assistant Professor Leukemia

English Text Solid Tumors: Diagnosing and Staging Part 1: Leukemias and Myelodysplastic Syndrome VideoTranscript Professional Oncology Education Solid Tumors: Diagnosing and Staging Part 1: Leukemias and Myelodysplastic Syndrome Time: 35:13 Tapan Kadia, M.D. Assistant Professor Leukemia The University of Texas MD Anderson Cancer Center Hello, everyone. My name is Tapan Kadia. And today, I will be talking to you about hematologic malignancies, the diagnosis and staging. I am an Assistant Professor at the Department of Leukemia at the University of Texas MD Anderson Cancer Center. And as part of this, the first part of this lecture, we will talk about leukemias and myelodysplastic syndrome. But before we start, we are going to talk about the normal hematopoietic system, the production of red blood cells, white blood cells, and platelets; go on to disease states such as cytopenias, and then on to leukemias.

Spanish Translation Tumores sólidos: diagnóstico y estadificación Parte 1: Leucemias y síndrome mielodisplásico Transcripción del video Educación Oncológica Profesional Tumores sólidos: diagnóstico y estadificación Parte 1: Leucemias y síndrome mielodisplásico Duración: 35:13 Dr. Kadia Tapan Profesor Adjunto Leucemia MD Anderson Cancer Center de la Universidad de Texas Hola a todos. Mi nombre es Tapan Kadia, y voy a hablar acerca de enfermedades hematológicas malignas, su diagnóstico y estadificación. Soy Profesor Adjunto en el Departamento de Leucemia del MD Anderson Cancer Center de la Universidad de Texas. En la primera parte de esta disertación hablaremos de las leucemias y el síndrome mielodisplásico. Nos referiremos al sistema hematopoyético normal, la producción de glóbulos rojos, glóbulos blancos y plaquetas, para luego hablar de enfermedades como las citopenias, y por último las leucemias.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Objectives

Upon completion of this lesson, participants will be able to: • Discuss the normal hematologic systems

So, these are some of the objectives for the entire module. Upon completion of this lesson, we should be able to talk about: the normal hematopoietic system; identify common presenting symptoms for hematologic malignancies; and then discuss initial diagnosis and staging for leukemias, MDS or myelodysplastic syndrome, lymphomas, and multiple myeloma.

Estos son los objetivos para todo el módulo. Al finalizar esta lección, podremos hablar sobre el sistema hematopoyético normal; identificar los síntomas comunes que presentan las condiciones hematológicas malignas; y luego discutir el diagnóstico inicial y la estadificación de las leucemias, síndrome mielodisplásico o MDS, linfomas y mieloma múltiple.

As part of the first module, as I mentioned, I will go over the normal hematopoietic system. We will discuss the presentation, diagnosis, and staging for acute myelogenous leukemia or AML, acute lymphocytic leukemia or ALL, chronic myelogenous leukemia or CML, and chronic lymphocytic leukemia or CLL. And we'll also talk about the difference between myelodysplastic syndrome and acute myeloid leukemia, and the specific diagnostic characteristics to distinguish between the two.

En la primera parte me referiré al sistema hematopoyético normal. Hablaremos de la presentación, el diagnóstico y la estadificación de la leucemia mieloide aguda o AML, la leucemia linfocítica aguda o ALL, la leucemia mieloide crónica o CML, y la leucemia linfocítica crónica o CLL. También veremos la diferencia entre el síndrome mielodisplásico y la leucemia mieloide aguda, así como las características específicas de diagnóstico para distinguirlos.

• Identify common presenting symptoms and signs for hematologic malignancies • Discuss the initial diagnosis and staging for leukemias, myelodysplastic syndrome, lymphomas, and multiple myeloma

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Part I: Objectives

• Review the normal hematologic system • Discuss the presentation, diagnosis, and staging for: – – – –

Acute myelogenous leukemia Acute lymphocytic leukemia Chronic myelogenous leukemia Chronic lymphocytic leukemia

• Distinguish myelodysplastic syndrome (MDS) from acute myeloid leukemia (AML)

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Blood

• A mixture of plasma and cells • Blood cells are made in the bone marrow • Types of cells in blood are: – White blood cells (WBC) – Red blood cells (RBC) – Platelets

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Normal Peripheral Blood

RBC WBC

Platelets

So, blood: blood is a mixture of plasma and cells and blood cells are made in the bone marrow. Throughout the adult life, bone marrow is mainly sequestered in the pelvic bones and the sternum. During birth, the bone marrow is sequestered in most long bones in the body. The bone marrow produces three types of cells, which make up the blood. And these are white blood cells, red blood cells, and platelets; each having their own function, which we will go into more detail in just a bit.

La sangre es una mezcla de plasma y glóbulos, y éstos se producen en la médula ósea. En la vida adulta, la médula ósea se encuentra retenida principalmente en los huesos de la pelvis y el esternón, pero al nacer, esto ocurre en casi todos los huesos largos del cuerpo. La médula ósea produce tres tipos de células que forman la sangre: glóbulos blancos, glóbulos rojos y plaquetas; cada una tiene su propia función, como ya detallaremos.

So, this is a typical peripheral blood smear, which represents the normal peripheral blood. As you can see there are three types of cells illustrated here. The red blood cells are listed here --- are illustrated here. These larger cells with multiple nuclei are white blood cells; in this case specifically polymorphonuclear leukocytes, which we'll get into in a bit. And these tiny little specks, which almost do not seem like cells, are in fact the platelets. Each one of these cells has its own function in the blood, which we will get into and then we will talk about disease states where these cells are low or malignant.

Este es un frotis típico de sangre periférica que representa la sangre periférica normal, y muestra tres tipos de células. Los glóbulos rojos están aquí. Estas células grandes con núcleos múltiples son los glóbulos blancos de la sangre, en este caso, leucocitos polimorfonucleares, y estas partículas diminutas, que casi no parecen células, son las plaquetas. Cada una de estas células tiene su propia función en la sangre. Me referiré a ellas y a enfermedades donde estas células son escasas o malignas.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Red Blood Cells (RBC)

• Packed with hemoglobin • Carry oxygen and carbon dioxide between the lungs and the rest of the body

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Platelets

• Small pieces of a large precursor cell called a megakaryocyte • Provides hemostasis and prevents bleeding

So red blood cells: red blood cells are those cells that are packed with hemoglobin, which is the molecule that is responsible for carrying oxygen and carbon dioxide between the lungs and the rest of the body. And so the red blood cells, they become oxygenated when they are transported to the lungs, when we take a deep breath. And then its oxygen is delivered to the rest of the body, the tissues that need oxygen such as muscles, brain, etc. The red blood cells and hemoglobin also pick up carbon dioxide, which is released from cellular metabolism, and bring them back to the lung where we are able to expire and release these toxic or waste gases into the rest of the atmosphere.

Los glóbulos rojos son células que contienen hemoglobina, la molécula que transporta oxígeno y dióxido de carbono entre los pulmones y el resto del cuerpo. Los glóbulos rojos se oxigenan al ser transportados a los pulmones, cuando inhalamos. El oxígeno se distribuye luego al resto del cuerpo, a los tejidos que lo necesitan, como los músculos, el cerebro, etc. Los glóbulos rojos y la hemoglobina también recogen el dióxido de carbono emitido por el metabolismo celular y lo llevan a los pulmones, y al exhalar, estos gases tóxicos o de desecho se liberan a la atmósfera.

Platelets are actually small pieces of a large precursor cell called the megakaryocyte, which is a factory type of cell, which exists in the bone marrow. Platelets are produced when portions of the cytoplasm of the megakaryocyte break off and go into the blood ---go into the blood stream. Platelets are very important in providing hemostasis and to prevent bleeding. And so low platelets can lead to bruising, bleeding, and other complications.

Las plaquetas son fragmentos de una célula precursora grande llamada megacariocito, una especie de fábrica celular que existe en la médula ósea. Las plaquetas se producen cuando partes del citoplasma del megacariocito se desprenden y pasan al torrente sanguíneo. Son muy importantes, ya que proveen la hemostasis para evitar el sangrado, y pueden dar lugar a hematomas, hemorragias y otras complicaciones.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

White Blood Cells (WBC)

• Different types of WBCs – specialized to fight different infections • Types of WBCs are: – – – – –

neutrophils lymphocytes eosinophils monocytes basophils

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Neutrophils • Also known as: ‘granulocytes’, ‘segs’, ‘PMNs’ (polymorphonuclear), and ‘polys’ • Fight common bacterial infections by: – Phagocytosis – Elaboration of toxic oxygen metabolites – Anti-bacterial enzymes

• First WBCs to appear at sites of infection or inflammation • Nonspecific; most target antigens need to be coated with antibodies or complement for efficient killing

Now, white blood cells are the most important part of our immune system. There are several different types of white blood cells that are specialized to fight different types of infection; and they are the first cells to present at the sites of inflammation. The different types of white blood cells are listed here: neutrophils, lymphocytes, eosinophils, monocytes, and basophils. We will briefly go through each of them and describe their function in a little bit of detail.

Los glóbulos blancos son el componente más importante de nuestro sistema inmunológico. Hay varios tipos de glóbulos blancos que se especializan en combatir distintas infecciones, y son las primeras células presentes en los sitios de inflamación. Los diferentes tipos de glóbulos blancos son: neutrófilos, linfocitos, eosinófilos, monocitos y basófilos. Hablaremos sobre cada uno de ellos y su función con más detalle.

Neutrophils are known by many different names. They are also called granulocytes or segs because of their segmented nuclei as can be seen here. They are also called PMNs or polymorphonuclear leukocytes or simply polys by hematologists. Neutrophils are often considered the "Marines" of the immune system because they are usually the first cells that appear at the site of an infection or inflammation. They fight common bacterial infections by several different mechanisms. Among them include phagocytosis, which literally means eating the cell, which they engulf foreign bacteria or other particles; elaboration of toxic oxygen metabolites, meaning they release things like hydrogen peroxide into the bacterial cell wall that kills the bacteria. And finally they are also able to produce anti-bacteria enzymes, which can digest bacteria and other organisms. As I mentioned, these are the first white blood cells to appear at sites of infection or inflammation. And, in fact, these are the cells that make up pus that we often see in cuts or --

Los neutrófilos se conocen con nombres diferentes. También se llaman granulocitos o segmentados, por sus núcleos segmentados, como se ve aquí. Los hematólogos también los llaman leucocitos polimorfonucleares (PMN) o simplemente “polis”. Se consideran los “soldados” del sistema inmunológico, ya que suelen ser los primeros en aparecer en el sitio de una infección o inflamación. Combaten infecciones bacterianas comunes con diferentes mecanismos, como la fagocitosis —literalmente se comen la célula, engullen bacterias extrañas y otras partículas—; la elaboración de metabolitos tóxicos del oxígeno —liberan peróxido de hidrógeno en la pared celular bacteriana, que mata las bacterias—; finalmente, también pueden producir enzimas antibacterias, que digieren bacterias y otros organismos. Estos son los primeros glóbulos blancos que aparecen en los sitios de infección o inflamación, y forman el pus que vemos en los cortes y otras lesiones. Los neutrófilos suelen ser inespecíficos. Atacan todo tipo de inflamación, y

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Lymphocytes • More specific, targeted • T-cells – – – –

CD4: ‘T-Helper’ CD8: ‘Cytotoxic T-cells’ Cell-mediated immunity Release cytokines

• B-cells – Produce antibodies as directed by T-cells

• Natural killer (NK) cells – Kill infected cells – Attack cancer cells

- other types of injuries. As I mentioned, neutrophils are most often nonspecific. They attack all types of inflammation. And most need that the targeted antigens are coated with antibodies or complement for better and efficient killing. As opposed to the lymph --- the neutrophils, the lymphocytes are more specific and more targeted. They are the "Special Forces", if you will, when describing it to kids. Since they are more specific, they are able to be differentiated and able to recognize different types of viruses, different types of virus-infected cells, and even different types of bacteria and fungi. There are two main types of lymphocytes: T-cells and B-cells. T-cells and B-cells are all derived from the original stem cell that helps derive hematopoietic cells. Later on in life as they mature, precursors of the T-cells go to the thymus gland and mature into T-cells, where precursors for the B-cells go into the bone marrow and mature later into B-cells. T-cells are mainly divided into two major categories, what we call CD4 type or helper T-cells, and CD8 type or cytotoxic T-cells. They are both involved in cell-mediated immunity. This means that the T-cells in fact associate directly with the foreign bacteria, virus-infected cell, or fungi to exert its cytotoxic effect. They can release cytokines, which can cause other immune cells to come to the site of infection and help in killing the foreign organism. B-cells on the other hand are not really involved in cytotoxic or cell-mediated immunity, but are involved in humoral immunity. What this means is that B-cells produce antibodies as directed by the T-cells that we just described. As a result, there are millions of types of B-cells each producing its own specific type of antibody, each directed at specific antigens, which the patient may or may not have been exposed to before. B-cells are the types of

necesitan que los antígenos objetivo estén recubiertos con anticuerpos o complementarse para combatirlos con más eficacia.

A diferencia de los neutrófilos, los linfocitos son más específicos y dirigidos. Son las “fuerzas especiales”. Como son más específicos, pueden diferenciarse y reconocer diferentes virus, diferentes células infectadas por virus, e incluso diferentes bacterias y hongos. Hay dos tipos principales de linfocitos: células T y células B. Ambas se derivan de la célula madre original que ayuda a producir células hematopoyéticas. Luego, las precursoras de las células T van al timo y maduran para convertirse en células T, en tanto que las precursoras de las células B entran a la médula ósea, maduran y se convierten en células B. Las células T se dividen en dos categorías principales: las de tipo CD4 o células T auxiliares, y las de tipo CD8 o células T citotóxicas. Ambas participan en la inmunidad mediada por células. Las células T se asocian directamente con bacterias extrañas, células infectadas por virus u hongos para ejercer su efecto citotóxico. Pueden liberar citocinas, lo cual atrae hacia la infección a otras células inmunes que ayudan a combatir los organismos extraños. Las células B no participan en la inmunidad citotóxica o mediada por células, pero sí en la inmunidad humoral. Así, las células B producen anticuerpos dirigidas por las células T. En consecuencia, hay millones de tipos de células B que producen su propio tipo específico de anticuerpos, cada uno dirigido a antígenos específicos a los cuales el paciente puede o no haber estado expuesto. Las células B son las que nos dan la memoria a largo plazo para muchas de las infecciones infantiles que

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Monocytes and Macrophages • Play a role killing yeasts, fungi, and unusual bacteria such as listeria • Also responsible for granulomatous reactions such as tuberculosis

Monocyte

• Macrophages are monocyte derived phagocytic cells that primarily reside in various tissues Macrophage engulfing debris and a PMN

cells that give us long-lasting memory to many of the different type of childhood infections that we have had. And B-cells are the types of cells that react to vaccinations that we have had both in childhood and as adults. A subset of T-cells known as natural killer cells are a specialized type of T-cell, which can kill infected cells and attack cancer cells and are also active by cell-mediated or cytotoxic immunity. Next, we go on to the monocyte lineage. Monocytes are larger white blood cells, which are different than lymphocytes and neutrophils. And they play an important role in killing yeast, fungi, and usual intracellular bacteria, such as listeria. They are also responsible for causing granulomatous infections, such as tuberculosis in patients who are infected with those. They often engulf the bacteria, or viruses, or fungi, or yeast, and form granuloma around them as their type of inflammation. Macrophages are a type of monocyte-derived cell which is more involved in phagocytosis. And they primarily resolve --- reside in various tissues, such as the lung or the soft tissue; whereas monocytes are often seen circulating in the blood stream. This is a picture of megakaryocyte, for example, that is engulfing various cells around it. As you can see here, this small cell within the cytoplasm of the megakaryocyte represents a polymorphonuclear leukocyte, which has perhaps been dying after being --- after attacking a foreign organism.

hemos tenido, y reaccionan a las vacunas que recibimos en la infancia y en la edad adulta. Hay un tipo especializado de células T, conocidas como asesinas naturales, que pueden matar células infectadas y atacar células cancerosas, y que también se activan por la inmunidad citotóxica o mediada por células.

Pasemos a la estirpe de los monocitos. Son glóbulos blancos más grandes, diferentes de los linfocitos y los neutrófilos. Cumplen una importante función al matar levaduras, hongos y bacterias intracelulares comunes, como la listeria. También son responsables de causar infecciones granulomatosas, como la tuberculosis, en pacientes infectados. Suelen engullir bacterias, virus u hongos y levaduras y forman granulomas en torno a ellos, como su tipo de inflamación. Los macrófagos son células derivadas de monocitos, más involucrados en la fagocitosis. Residen en diversos tejidos, como el pulmón o el tejido blando, mientras que los monocitos suelen circular en el torrente sanguíneo. Esta es una foto de un megacariocito engullendo varias células a su alrededor. Esta pequeña célula en el citoplasma del megacariocito es un leucocito polimorfonuclear que tal vez esté muriendo luego de atacar a un organismo extraño.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Eosinophils

• Responsible for immune reaction to parasites • Also involved in allergic response

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Basophils

• Involved in allergic response by releasing chemical mediators

Next, we have eosinophils. Eosinophils are very easy to spot in the peripheral blood smear as they have a very red-looking cytoplasm. And on higher magnification you will notice that these red cytoplasms are actually made up of small red granules which are full of enzymes that help the eosinophil do its job. Eosinophils are very important in the immune reaction against the parasites such as worms and other things. They are also very involved in allergic response. Therefore, in patients with a very elevated eosinophil count, it is always important to look for, or think about parasitic infection or a recent allergic response.

Luego tenemos los eosinófilos. Son muy fáciles de ver en el frotis de sangre periférica, ya que tienen un citoplasma muy rojo. Con más aumento, se verá que estos citoplasmas rojos constan de pequeños gránulos de color rojo colmados de enzimas que ayudan a los eosinófilos a realizar su tarea. Los eosinófilos son muy importantes en la reacción inmune contra los parásitos, como gusanos y otros patógenos. También participan activamente en la respuesta alérgica. Por eso, un recuento de eosinófilos muy alto puede indicar una infección parasitaria o una reacción alérgica recientes.

Finally, we have basophils, also involved in allergic response because they release the different chemical mediators. And basophils are suspicious cells, which are not often seen in normal peripheral blood smear, but are elevated in certain malignant conditions such as chronic myelogenous leukemia.

Por último tenemos los basófilos, que también participan en la respuesta alérgica porque liberan diferentes mediadores químicos. Son células sospechosas que no suelen verse en el frotis de sangre periférica normal, pero aumentan con ciertas enfermedades malignas, como la leucemia mielógena crónica.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Lymphatic System • Lymphocytes • Lymphoid organs – – – – – –

Bone marrow Thymus Lymph nodes Spleen Tonsils, adenoids Digestive and respiratory tracts

• Lymphocyte circulation

Adenoid Tonsil Lymph nodes Thymus gland Thoracic duct Lymphatics Spleen Peyer’s patch in small intestine Appendix Bone marrow

Before we go on, let us talk about the normal lymphatic system. Now, we know that the normal lymphatic system is made up of lymphocytes, which are the T-lymphocytes and the B-lymphocytes. They not only reside in the bone marrow, but they have many other sites throughout the body. The thymus, which we know is the area where T-cells mature, lymph nodes, which are present throughout our body as shown here in this diagram. The green nodules here represent the lymph nodes, which are up and down our body and are connected by a series of channels, what we call lymphatic circulation. The spleen is also an important site, which is located in the left upper quadrant, but it is an important site for --- lymph node --- trafficking. Finally, the tonsils and adenoids are also lymphoid glands. And the entire digestive and respiratory tract are lined with small patches in the --- small Peyer's patches and other nodules, which contain large amounts of lymphocytes, which work to help surveillance against infections and local localized inflammation. Lymphocyte circulation occurs between these lymph glands, the spleen, the gastrointestinal system through the lymphatic channels, which I described.

Antes de continuar, hablemos sobre el sistema linfático normal. Se compone de linfocitos T y linfocitos B. No sólo residen en la médula ósea, sino que se alojan en muchos otros sitios del cuerpo, como el timo —el área donde las células T maduran— y los ganglios linfáticos, presentes en todo el organismo, como se muestra en este diagrama. Estos nódulos verdes son los ganglios linfáticos, presentes en todo el organismo y conectados por una serie de canales llamados circulación linfática. El bazo, situado en el cuadrante superior izquierdo, también es un sitio importante para este tráfico. Por último, las amígdalas y las adenoides también son glándulas linfoides. Todo el tracto digestivo y respiratorio está revestido de pequeñas placas de Peyer y otros nódulos, con grandes cantidades de linfocitos que ayudan proteger contra infecciones e inflamación localizada. La circulación de linfocitos se produce entre estos ganglios linfáticos, el bazo y el sistema gastrointestinal a través de estos canales linfáticos.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Types of Cytopenias

• Leukopenia – low WBC – Predispose patients to infection by opportunistic organisms

• Anemia – low RBC – Shortness of breath, fatigue, cardiovascular complications

• Thrombocytopenia – low platelets – Risk for bruising/bleeding (bleeding gums, epistaxis, petechiae, ecchymoses, or internal bleeding)

So, now that we've talked a little bit about the normal hematopoietic system and where these cells reside, we should talk about some of the disease states. And, of course, one of the main disease states we need to discuss are cytopenias or low blood counts. This is often a common presentation that is seen in many patients in internal medicine offices or even patients who are seen by hematologists. The three types of cytopenias obviously are low white blood cell count or leukopenia, low red blood cell count or anemia, or low platelet count or known as thrombocytopenia. Low white cells can predispose patients to infections by other different organisms. Low red blood cell count will lead to anemia and will lead to shortness of breath, fatigue, and cardiovascular complications, as there will be a mismatch between the amount of oxygen needed and the amount of oxygen that is able to be transported by the blood. Low platelet count, as we mentioned before, puts you at a very high risk for bruising, bleeding. And this can result in bleeding gums, epistaxis, petechiae or small red rash all over your body, ecchymosis, or bruising, and internal bleeding. So, it is very important to watch for low platelet count, especially when they drop below 50,000, as this puts you at a very high risk for bleeding, spontaneous bleeding, especially the worrisome intracranial hemorrhages.

Nos hemos referido al sistema hematopoyético normal y dónde residen estas células; veamos ahora algunas enfermedades. Unas de las principales son las citopenias o bajos recuentos de glóbulos sanguíneos, que se observan en muchos pacientes en consultorios de medicina interna, o incluso en pacientes atendidos por hematólogos. Los tres tipos de citopenias son: bajo recuento de glóbulos blancos o leucopenia; bajo recuento de glóbulos rojos o anemia; y bajo recuento de plaquetas, denominado trombocitopenia. Un bajo nivel de glóbulos blancos puede predisponer a los pacientes a infecciones por otros tipos de organismos. El bajo recuento de glóbulos rojos da lugar a la anemia, falta de aliento, fatiga y complicaciones cardiovasculares, ya que hay un desfase entre la cantidad de oxígeno necesaria y la que puede ser transportada por la sangre. El bajo recuento de plaquetas conlleva un riesgo muy alto de hematomas y hemorragia. Esto puede dar lugar a sangrado de las encías, epistaxis, petequias — una pequeña erupción roja en todo el cuerpo—, equimosis o hematomas; y hemorragias internas. Es muy importante vigilar el bajo recuento de plaquetas, sobre todo si es inferior a 50,000, ya que genera un riesgo muy alto de hemorragias y sangrado espontáneo, especialmente las alarmantes hemorragias intracraneales.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Evaluation of Cytopenias

• Peripheral blood smear • Role of bone marrow aspiration/biopsy • Underproduction – – – – –

Myelodysplastic syndrome Aplastic Anemia Vitamin deficiencies Viral Bone marrow infiltration

So, how does one evaluate cytopenias? And the first step we often do after doing the CBC and realizing there is cytopenia is to look at a peripheral blood smear. There are many clues in the morphology of the red blood cells, the white blood cells, and sometimes even clumping of the platelets that gives us an idea why the cytopenias may be occurring. The next step often is to look at a bone marrow aspiration or biopsy. And the reason for this is to try to figure out the etiology of the cytopenia, whether it is due to underproduction, where the bone marrow is not producing good blood cells or whether it is due to increased peripheral destruction. In other words, is the bone marrow completely normal and producing normal cells? And are these cells being destroyed elsewhere in the body? So this is an important distinction that needs to be made in the initial evaluation of cytopenias because the diseases are very different and the treatments are very different. Certain examples of underproduction are: myelodysplastic syndrome, which we will talk a little bit about later; aplastic anemia, in which the bone marrow is completely empty and devoid of any hematopoietic elements due to many different causes; vitamin deficiencies, such as iron deficiency, B12 deficiency,or folate deficiency, which can all lead to anemia and some can also lead to leukopenia and thrombocytopenia; viral infections, such as HIV, hepatitis A, B, and C as well as CMV and Epstein-Barr virus, and other childhood viruses can actually lead to bone marrow damage and destruction on a temporary basis leading to a relatively aplastic marrow and low blood counts. Finally bone marrow infiltration is an important thing to realize when doing a bone marrow aspiration and biopsy in the evaluation of cytopenias. The bone marrow can be infiltrated with

¿Cómo evaluar las citopenias? Lo primero que hacemos si un hemograma completo indica citopenia es obtener un frotis de sangre periférica. Hay muchos indicios en la morfología de los glóbulos rojos, los glóbulos blancos, y a veces incluso en el agrupamiento de las plaquetas, que pueden sugerirnos por qué ocurre la citopenia. El paso siguiente es a menudo hacer una aspiración o biopsia de médula ósea para tratar de averiguar la etiología de la citopenia, ya sea que la médula ósea no esté produciendo buenas células sanguíneas o exista una mayor destrucción periférica. En otras palabras, ¿es la médula ósea completamente normal y produce células normales? ¿Están estas células destruyéndose en otras partes del organismo? Esta es una distinción importante al evaluar inicialmente las citopenias, porque las enfermedades y los tratamientos son muy diferentes. Algunos ejemplos de baja producción son: el síndrome mielodisplásico, del cual hablaremos más adelante; la anemia aplásica, en donde la médula ósea está completamente vacía y carece de elementos hematopoyéticos debido a muchas causas; las deficiencias de vitaminas, como hierro y vitamina B12 o folato, que pueden causar anemia y hasta leucopenia y trombocitopenia; las infecciones virales, como VIH, hepatitis A, B y C, citomegalovirus, virus de Epstein-Barr y otros virus de la infancia, que pueden producir daños y destrucción temporales de la médula ósea, y provocar una médula relativamente aplásica y bajos recuentos sanguíneos. Por último, es importante considerar la infiltración de médula ósea cuando se hace una aspiración y biopsia de la médula ósea para evaluar las citopenias. La médula ósea puede ser infiltrada por diferentes patógenos, incluso infecciones como levaduras o histoplasma;

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Evaluation of Cytopenias

• Peripheral consumption/destruction – – – –

Autoimmune destruction Sequestration DIC Mechanical

many different things including infections such as yeast or histoplasma; malignancies such as breast cancer, prostate cancer, thyroid cancer, and others; or a fibrosis in the case of myelofibrosis. The other arm of evaluating cytopenias: if it's not underproduction in the bone marrow then we look for peripheral consumption and destruction. Usually in these states, the bone marrow is actually relatively normal or even hypercellular, meaning that the bone marrow is trying to compensate for the low cytopenias. And this can occur due to: autoimmune destruction, where the immune system outside the bone marrow is destroying the blood cells; sequestration in patients who have a large liver or spleen where the blood cells are residing and, therefore, out of the circulation; DIC or disseminated intravascular coagulation, in which the body is clotting incessantly and using up or consuming platelets and other factors causing a lower blood count; or mechanical problems, such as heart valves or other things, which cause shear stress and destroy these red --- destroy these blood cells on a more mechanical or physical level.

enfermedades malignas como el cáncer de mama, cáncer de próstata, cáncer de tiroides y otros; o una fibrosis, en el caso de mielofibrosis. Si no hay baja producción en la médula ósea, lo siguiente es comprobar si hay consumo y destrucción a nivel periférico. En estos casos, la médula ósea suele ser relativamente normal o incluso hipercelular, porque procura compensar la citopenia. Esto puede ocurrir debido a la destrucción autoinmune, donde el sistema inmunológico externo a la médula ósea destruye las células sanguíneas; retención celular en pacientes con hígado o bazo agrandados, donde las células sanguíneas residen y, por lo tanto, quedan fuera de circulación; coagulación intravascular diseminada, o DIC, donde el organismo coagula sin cesar, agota las plaquetas y otros factores, y reduce el recuento sanguíneo; o problemas mecánicos, como válvulas cardíacas u otros, cuyas fuerzas hemodinámicas destruyen las células sanguíneas a nivel mecánico o físico.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Blood Cells

So just as a review, before we go on to the malignant portion of this talk, looking at the malignant types of hematopoietic disorders, let's go over the family tree, if you will, of hematopoietic lineage. On the left, we have what is called the very immature or early precursors of the different types of blood cells, and [on] the right side we have the mature or functional or active arm of the hematopoietic system. As we go from the immature and grow or mature into the more mature forms we lose proliferative capacity meaning they are able to -- they are less able to proliferate and divide rapidly, but we increase their functional capacity; in this case, fighting infection or engulfing organisms, or in this case, producing antibodies. So, if we start off there is hematopoietic stem cell, which often divides into myeloid and lymphoid lineages, the myeloid lineage, which can later on give rise to myeloid malignancies, such as AML or CML, can differentiate into red cells or granulocytes --granulocytes/monocytes and give rise to these as mature cells. The lymphoid derivative of a stem cell often gives rise to T-cells and B-cells and can also give rise to lymphoid malignancies such as ALL or CLL.

Antes de pasar a los tumores malignos y referirnos a los trastornos hematopoyéticos, repasemos el árbol genealógico hematopoyético. A la izquierda tenemos los precursores, muy inmaduros o incipientes, de los diferentes tipos de células sanguíneas; y a la derecha tenemos la rama madura, funcional o activa del sistema hematopoyético. A medida que las células pasan de la inmadurez a las formas más maduras, pierden la capacidad proliferativa —proliferan y se dividen con menos rapidez, pero aumentan su capacidad funcional—; en este caso, para combatir infecciones y absorber organismos; en este otro, para producir anticuerpos. Partimos de una célula madre hematopoyética, que a menudo se divide en linajes mieloide y linfoide. El mieloide, que posteriormente puede causar condiciones mieloides malignas, como AML o CML, puede diferenciarse en glóbulos rojos o granulocitos y monocitos, y dar lugar a estas células maduras. El derivado linfoide de una célula madre suele generar células T y células B, y también dar lugar a condiciones linfoides malignas como ALL o CLL.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Leukemia

• A group of neoplastic diseases characterized by abnormal proliferation of white blood cells

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Types of Leukemia

• Acute leukemias: characterized by proliferation of immature precursors in blood and marrow • Chronic leukemias: characterized by proliferation of mature precursors • Myeloid leukemias: characterized by cells with characteristics similar to myeloid cells or their precursors • Lymphoid leukemias: characterized by cells with characteristics similar to lymphoid cells or their precursors

So, leukemia, in general, is a group of neoplastic diseases characterized by abnormal proliferation of white blood cells because they are malignant and they are no longer subject to the normal cell division processes.

La leucemia es, en general, un grupo de enfermedades neoplásicas caracterizadas por la proliferación anormal de glóbulos blancos, que son malignos y no intervienen en los procesos normales de división celular.

So, the different types of leukemias are acute leukemias and chronic leukemias. Acute leukemias are generally rapidly progressive diseases that are characterized by proliferation of immature precursors in the bone marrow and the blood, and immature meaning, if you remember the left side of that particular family tree, the earlier precursors. Chronic leukemias, on the other hand, are characterized more by proliferation of the mature precursors. So the defect in the actual leukemic cells is later on in the family tree where the actual white blood cell has matured somewhat. Myeloid leukemia as we talked about characterized by cells with characteristics similar to myeloid cells or their precursors. And lymphoid leukemias are characterized by cells with characteristics similar to lymphoid cells or their precursors.

Las leucemias pueden ser agudas o crónicas. Las agudas son enfermedades de progresión rápida, con proliferación de precursores inmaduros en la médula ósea y la sangre; por inmaduros, nos referimos a los primeros precursores, a la izquierda del árbol genealógico. Las leucemias crónicas, en cambio, se caracterizan más por la proliferación de precursores maduros. El defecto en las células leucémicas se produce en una etapa posterior del árbol genealógico, cuando el glóbulo blanco ha tenido cierta maduración. La leucemia mieloide está determinada por células con características similares a las células mieloides o sus precursores, y las leucemias linfoides por células con características similares a las células linfoides o sus precursores.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Types of Leukemia

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Four Major Types of Leukemia

This is an example of a peripheral blood smear of someone with acute leukemia. Notice that these are very immature-looking cells because they are large. They have very large nucleus with some nucleoli within them. And this is often a rapidly progressive disease.

Este es un frotis de sangre periférica de un paciente con leucemia aguda. Estas células tienen un aspecto muy inmaduro, pues son grandes. Tienen un núcleo muy grande, con algunos nucléolos en su interior. Esta suele ser una enfermedad de progresión rápida.

So, the four major types of leukemia, as we outlined before: ALL, AML, CML, and CLL. We will briefly go through these in the next few slides.

Los cuatro tipos principales de leucemia son ALL, AML, CML y CLL. Las analizaremos brevemente en las próximas diapositivas.

• Acute lymphocytic (ALL) • Acute myelogenous (AML) • Chronic myelogenous (CML) • Chronic lymphocytic (CLL)

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Symptoms of Leukemia

• Non-specific symptoms • Acute leukemia patients present with: – – – –

Malaise/fatigue Fever Anemia Bone Pain

– Flu-like symptoms – Opportunistic infections – Bleeding

• Chronic leukemia patients present with: – Malaise/fatigue – Splenomegaly – Weight loss – Lymphadenopathy – May be asymptomatic; incidental finding

So, the symptoms, in general, of leukemias are presented here. They're very nonspecific. Acute leukemia symptoms are generally not subtle. They are usually very, very aggressive and patients often present very sick to the hospital with symptoms such as: severe malaise and fatigue; high fevers; symptoms of anemia such as shortness of breath and severe fatigue; bone pain, as the leukemia is growing rapidly within the bone marrow, stretching the cortical bone causing severe bone pain. Many may have flu-like symptoms. Many may have opportunistic infections due to the immune defect that is associated. And in many cases, due to severe thrombocytopenia or DIC there may be bleeding complications. Chronic leukemia patients, on the other hand, may be somewhat asymptomatic in many cases. And the finding of leukemia may be an incidental finding, especially in the cases of CLL. But once again many of these patients especially in the more advanced stages will present with malaise, fatigue, weight loss. And, in --- unlike the acute leukemias, more commonly present with things like splenomegaly and lymphadenopathy, which are associated with CML and CLL, respectively.

Aquí se presentan los síntomas generales de las leucemias. Son muy inespecíficos. Los síntomas de la leucemia aguda no suelen pasar inadvertidos. Son muy agresivos, y los pacientes a menudo se presentan en el hospital con síntomas como malestar general y fatiga severa; fiebre alta; síntomas de anemia, como falta de aliento y fatiga severa; dolor óseo, pues la leucemia avanza rápidamente en la médula ósea y estira el hueso cortical, causando dolor óseo severo. Muchos pacientes pueden tener síntomas similares a la gripe, o manifestar infecciones oportunistas debido al defecto inmunológico asociado. En muchos casos de trombocitopenia grave o DIC, puede haber complicaciones hemorrágicas. Los pacientes con leucemia crónica, en cambio, pueden ser asintomáticos en muchos casos. La leucemia puede ser un hallazgo incidental, especialmente en los casos de CLL. Sin embargo, muchos de estos pacientes, especialmente en las etapas más avanzadas, presentan malestar general, fatiga y pérdida de peso. A diferencia de las leucemias agudas, suele haber esplenomegalia y adenopatías, asociadas con CML y CLL, respectivamente.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Diagnosis of Leukemia

• Peripheral blood can reveal: – Elevated WBC – mature or immature forms – Anemia, thrombocytopenia

• Diagnosis is confirmed by bone marrow aspiration • Bone marrow findings: – Normal hematopoiesis is replaced by a monotonous infiltrate of immature blasts, mature WBC forms, or a mixture

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Acute Lymphocytic (ALL) – Overview

• Most common leukemia in children, although there are more adults with the disease than children FAB classification: L1 – small regular lymphoblasts L2 – larger and more regular blasts L3 – vacuoles in a basophilic cytoplasm Phenotypically: Pre-B, TdT, Calla, CIg Pre-T, TdT, CD2, 4, 5, 7, 8 – mediastinal mass B-SIg, t(2;8), t(8;14), t(8;22) – [Burkitt’s]

So, on diagnos – on diagnosing leukemia, the peripheral blood cell can often reveal elevated white blood cell with mature or immature forms like we saw in the previous --- two slides ago. We can also see anemia and thrombocytopenia on the peripheral blood. The diagnosis of these diseases is confirmed by a bone marrow aspiration looking at a --- a monotonous infiltrated immature blasts in the case of acute leukemias or mature white blood cell forms in the case of chronic leukemias that replaces the normal hematopoiesis that should be there.

En la leucemia, la sangre periférica a menudo muestra un aumento de glóbulos blancos maduros o inmaduros, como ya vimos. También puede haber anemia y trombocitopenia en la sangre periférica. El diagnóstico de estas enfermedades se confirma con una aspiración de médula ósea para detectar una infiltración monótona de blastos inmaduros, en el caso de las leucemias agudas o, para leucemias crónicas, glóbulos blancos maduros que reemplazan una hematopoyesis normal insuficiente.

So, ALL or acute lymphocytic leukemia, is the most common leukemia in children. Although there are more adults with the disease than there are children with the disease because of the --- because of the longer life of adults, and the fact that many patients --- many children with ALL are often cured of the disease. The older classification is the FAB classification is what is used currently, but is slowly being --- teased out --- phased out. It has basically three different subcategories that we call L1, L2 and L3, and they basically describe the morphology. As we become more advanced with our biological or molecular biologic techniques, it has become more important to look at the flow cytometry of these cells as well as the cytogenetics or the chromosomes and some molecular markers. Phenotypically, we can talk about three big categories of ALL or acute lymphocytic leukemia, and these are:

La leucemia linfocítica aguda, o ALL, es la más común en los niños, pese a que hay más adultos que la padecen; esto se debe al mayor tiempo de desarrollo y a que muchos niños con ALL suelen curarse. La clasificación más antigua es la FAB, que si bien actualmente se utiliza, está cayendo en desuso. Establece tres categorías denominadas L1, L2 y L3, que básicamente describen la morfología. Con el desarrollo de las técnicas biomoleculares, es cada vez más importante tener en cuenta la citometría de flujo de estas células, así como la citogenética, los cromosomas y algunos marcadores moleculares. Fenotípicamente, podemos hablar de tres grandes categorías de leucemia linfocítica aguda o ALL:

• Pre-B ALL, which is perhaps the most common. These are often positive for markers such as TdT,

• ALL pre-B, tal vez la más común, que suele ser positiva para marcadores como TdT, Calla, e IgG citoplasmáticos.

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Calla, and cytoplasmic IgG. • Pre-T-cell ALL, or ALL that is derived from T-cell lymphocyte or early T-cell lymphocytes, are often positive for these markers. And clinically they often present with a large mediastinal mass, as the only site of disease.

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

ALL – Overview CNS Disease:

High WBC High LDH

Extra Medullary:

Gonads Mediastinal mass Lymphadenopathy

• Finally, we have what is called the mature B-cell ALL, also known as Burkitt's leukemia/lymphoma, which is a very rapidly progressive disease that can be life threatening and must be treated immediately. Burkitt's leukemia/lymphoma is characterized by characteristic translocation involving chromosome 8, which has the myc oncogene. So we often see translocation t(2;8), t(8;14), or translocation t(8;22) as part of the disease that helps confirm the diagnosis of Burkitt's leukemia. ALL is notable in that it has a high incidence of CNS disease or disease involving the central nervous system. Factors associated with/or prognostic for CNS involvement is a high initial white blood cell count at presentation and a high LDH at presentation. As a result of the CNS disease, just as an aside, the treatment of ALL involves the treatment --- involves intrathecal therapy or therapy within the cerebral spinal fluid to not only treat, but also to prevent further infiltration into the CNS. ALL can also present very commonly with extramedullary disease. Often sites of involvement are gonads, mediastinal mass, as we talked about in T-cell ALL, as well as lymphadenopathy.

• ALL de células pre-T, derivada de linfocitos de células T o de células T incipientes, que suele ser positiva a estos marcadores. Clínicamente se presenta a menudo con una masa mediastínica grande, como único sitio de enfermedad. • Por último, tenemos la ALL de células B maduras, también conocida como leucemia o linfoma de Burkitt, una enfermedad de progresión muy rápida que puede ser potencialmente mortal y debe tratarse de inmediato. La leucemia o linfoma de Burkitt resulta de una translocación característica del cromosoma 8, que tiene el oncogén myc. A menudo vemos translocaciones t(2;8), t(8;14) o t(8;22) como parte de la enfermedad, lo cual ayuda a confirmar el diagnóstico de leucemia de Burkitt.

La ALL tiene una alta incidencia de enfermedades que afectan el sistema nervioso central o CNS. Los factores asociados con el compromiso del CNS o con su pronóstico son un alto recuento inicial de glóbulos blancos y un alto nivel inicial de LDH. Como resultado de la enfermedad del CNS, el tratamiento de la ALL requiere terapia intratecal, dentro del líquido cefalorraquídeo, no sólo para tratar sino también para evitar una mayor infiltración en el CNS. La ALL también puede presentarse con enfermedad extramedular. Los sitios comprometidos suelen ser las gónadas y la masa mediastínica, como en el caso de la ALL de células T, y los nodos linfáticos.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

ALL – Incidence and Mortality 90

6

5

75

4

60

3

45

2

30

1

15

0 0-4 5-9 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 8014 19 24 29 34 39 44 49 54 59 64 69 74 79 84

Mortality (per 100,000)

Incidence (per 100,000)

Median age 13 years (SEER 2008)

This picture illustrates the demographics and the incidence of mortality of patients with ALL. As you see, there are two big peaks: a peak in the very young age, as you can see in this peach-colored background, and a peak in the elderly. However, what you will see in the solid blue line is that the mortality increases as you get older and the mortality is relatively low in patients with young age because, in fact, the leukemia, ALL in younger adults or in kids is very responsive to chemotherapy, has a better prognosis, and a very high cure rate.

Este gráfico ilustra la demografía y la incidencia de la mortalidad de los pacientes con ALL. Hay dos grandes picos: uno a una edad temprana, como se puede ver en este fondo de color pardo, y un pico en las personas mayores. Sin embargo, la línea de color azul muestra que la mortalidad aumenta con la edad y que es relativamente baja en pacientes jóvenes, ya que la ALL en adultos jóvenes y en niños responde bien a la quimioterapia, tiene un mejor pronóstico y una tasa de curación muy alta.

The clinical presentation of ALL is listed here: again signs and symptoms of pancytopenia, such as risk of infection, bleeding, severe fatigue; bone pain, due to progressive leukemia; organomegaly, as we discussed; and the leukemia can infiltrate the liver, spleen, and lymph nodes. SVC syndrome or superior vena cava syndrome can occur from mediastinal lymphadenopathy that can often happen as the presenting sign of T-cell ALL. Neurologic symptoms may also be presenting signs such as a facial droop, aphasia, or other stroke-like symptoms because of CNS disease. Leukocytosis may occur with white counts of 100 to 200,000. But leukostasis, where the elevated white blood cell count causes neurologic or pulmonary symptoms is pretty rare. There are also metabolic abnormalities associated with advanced leukemia such as Tumor Lysis Syndrome. We have elevated potassium, elevated uric acid, and sometimes worsening kidney function.

Clínicamente, la ALL presenta signos y síntomas de pancitopenia, como riesgo de infección, hemorragia y fatiga severa; dolor óseo por leucemia progresiva; organomegalia, con posibilidad de infiltrarse en el hígado, el bazo y los ganglios linfáticos. Puede haber síndrome de vena cava superior (SVC) a partir de adenopatía mediastínica, que ocurre a menudo como signo característico de la ALL de células T. La enfermedad del CNS puede causar síntomas neurológicos, como parálisis facial, afasia y otros similares a los del ACV. Puede ocurrir leucocitosis, con recuentos de glóbulos blancos de 100 a 200,000, pero cuando este aumento causa síntomas neurológicos o pulmonares, la leucostasis es poco frecuente. Hay alteraciones metabólicas asociadas a la leucemia avanzada, como el síndrome de lisis tumoral, con potasio y ácido úrico elevados, y a veces deterioro de la función renal.

0 85+

Age group (Years) www.seer.cancer.gov

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

ALL – Clinical Presentation

• Signs and symptoms of pancytopenia • Bone pain • Organomegaly – Liver, spleen, lymph nodes – SVC Syndrome from mediastinal LAD (T-ALL)

• Neurologic symptoms from CNS disease • Leukocytosis, but rarely leukostasis • Metabolic abnormalities, tumor lysis syndrome

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Cytogenetics in Adult ALL t(9;22) (20-30%) BCR-ABL

Diploid and others (30-40%)

7q35 (3-5%) TCR ß

14q11 (5%) TCR α/δ

8q24 (1-2%) C-MYC

TAL1 TAL2 LCK TAN1 LYL1 RHOM1 RHOM2 TCL1 HOX11 Ig κ Ig λ IG H

t(1;19) (5-7%) t(12;21)(1-2%) ETV6-CBFA2

E2A-PBX1

t(4;11) (57%)

9p21 (7-15%) P16/p14/p15

11q23 (3-4%) MLL

AF1P AF10 ENL ? ATM

Cytogenetics or chromosomes are very important in the diagnosis and now as well in the treatment of leukemia, not only ALL, but many other acute leukemias as well as chronic leukemias as we will be able to see in the next few slides. This pie chart shows a relative distribution of different cytogenetic abnormalities in adult ALL, which are important. I will point out a few that are quite important. As you can see, the most common is diploid or no cytogenetic abnormality. But the second most common is translocation t(9;22), also known as the Philadelphia chromosome. This is important because this translocation portends a very poor prognosis in patients of adult ALL and these patients, after receiving chemotherapy, should move forward with a stem cell transplant in their first remission. Other important subtypes are translocation t(4;11) or translocations involving 11q23, which in some incidences include translocation t(4;11). This is another subgroup of patients that also has a relatively poor prognosis and should consider getting aggressive high-dose therapy followed by stem cell transplant after they achieve a remission. On this end, translocation t(12;21), in fact, is associated with a better prognosis, as most often seen in younger kids.

La citogenética y los cromosomas son muy importantes en el diagnóstico y también en el tratamiento de la leucemia ALL y de muchas otras leucemias agudas y crónicas, como veremos más adelante. Este gráfico muestra una distribución relativa de diversas anormalidades citogenéticas en la ALL en adultos, que son importantes. Señalaré las más relevantes. La más común es la anormalidad diploide o no citogenética. La segunda es la translocación t(9;22), también conocida como cromosoma Filadelfia, ya que conlleva un muy mal pronóstico en pacientes de ALL adultos que, después de recibir quimioterapia, deberían recibir un trasplante de células madre en su primera remisión. Otros subtipos importantes son la translocación t(4;11) y las que afectan el gen 11q23, que a veces incluyen la translocación t(4,11). Este es otro subgrupo de pacientes con un pronóstico relativamente malo y que debería recibir una terapia agresiva de alta dosis, seguida por un trasplante de células madre luego de la remisión. En este extremo, la translocación t(12;21) se asocia con un mejor pronóstico, como se observa con frecuencia en los niños.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Prognostic Significance in ALL

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Acute Myelogenous (AML) – Overview

• Five times as common as ALL • FAB classification: – – – – – – – –

M0-peroxidase negative, myeloid markers M1-peroxidase positive, no differentiation M2-peroxidase positive, differentiation M3-APL M4-myelomonocytic M5-monocytic M6-erythroid M7-megakaryoblastic

This is a table looking at the types of chromosomes and the prognosis that they portend. As you can see, Philadelphia chromosome, which is not very common in kids, is much more common in adults and has a very low cure rate. Hyperdiploid or having more than 46 chromosomes has a high incidence in pediatrics and is also associated with a higher cure rate. Translocation t(12;21), another one that is associated with high pediatric incidence and a relatively high cure rate.

Esta tabla muestra los tipos de cromosomas y sus pronósticos. El cromosoma Filadelfia, que no es muy común en los niños pero sí en adultos, tiene una tasa de curación muy baja. Las células hiperdiploides o con más de 46 cromosomas tienen una alta incidencia pediátrica, y se asocian a tasas de curación más altas. La translocación t(12;21) se asocia con una alta incidencia pediátrica y una tasa de curación relativamente alta.

Now we will turn to AML or acute myelogenous leukemia. It's much more common in adults than ALL. And this is the FAB or French-American-British Classification that we have used for many, many years. And is currently used as more of a historical marker rather than used in treatment, except with the exception of M3 or APL, which is treated much differently and now has a very high cure rate. These are the FAB Classifications listed here.

Ahora veremos la leucemia mielógena aguda, o AML, mucho más común en adultos que la ALL. Esta es la clasificación franco-americano-británica, FAB, que se ha utilizado durante muchos años. Actualmente se utiliza más como marcador histórico y no tanto en el tratamiento, a excepción de M3 o APL, que se trata de manera muy diferente y ahora tiene una tasa de curación muy alta. Estas son las clasificaciones FAB.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

AML – Clinical Presentation • Rapidly worsening clinical symptoms (usually not subtle) • Bone marrow with ≥ 20% blasts, ≥ 3% of which are myeloperoxidase positive • Complications of pancytopenia – Fatigue, exercise intolerance, pallor, weakness – Bleeding, bruising, DIC – Infection, fever, neutropenia

• Bone pain • Leukocytosis, peripheral blasts (leukostasis) • Myeloid Sarcoma (extramedullary disease)

Again, the clinical presentation is similar to other acute leukemias, rapidly progressive and worsening clinical symptoms. A bone marrow that has greater than or equal to 20% blasts of which more than --greater than or equal to 3% are myeloperoxidase or MPO positive. This gives you the diagnosis of AML. This 20% blast is important because if it's less than 20% blasts, similar myeloid diseases are known as myelodysplastic syndrome according to the current classification system. This is an important way to distinguish acute myeloid leukemia from high-risk MDS. The comp --- the other presenting signs again are complications of pancytopenia that we discussed previously, bone pain due to progressive leukemia, leukocytosis or very elevated white blood cell count. The difference between AML and ALL is that, in patients with AML with a very high white blood cell count, they are at risk for leukostasis. And this essentially means that they can have complications in their pulmonary system, their neurologic system, and other areas due to very high white blood cell count, as the white cells are thought to be a little bit more "sticky" [quote-unquote] and because they have better adhesion to the endothelial cells and cause problems related to sludging in the arteries and capillaries. A relatively uncommon presentation of AML is something called a myeloid sarcoma in which there is an extramedullary presentation or mass associated with AML. And this can be anywhere in the body. They can also appear on the skin and this is known as leukemia cutis.

La presentación clínica es similar a otros tipos de leucemia aguda, con progresión rápida y empeoramiento de síntomas clínicos. Una médula ósea con un 20% o más de blastos, de los cuales 3% o más son mieloperoxidasa- o MPO-positivos. Esto indica un diagnóstico de AML. Este 20% de blastos es importante porque, si es inferior, se trata de una enfermedad mieloide similar: el síndrome mielodisplásico, de acuerdo con el actual sistema de clasificación. Esto es importante para distinguir la leucemia mieloide aguda del MDS de alto riesgo. Los otros signos son las complicaciones de pancitopenia ya mencionadas, dolor óseo por leucemia progresiva, leucocitosis o alto nivel de glóbulos blancos. La diferencia entre la AML y la ALL es que, en los pacientes con AML que tienen un muy alto nivel de glóbulos blancos, hay riesgo de leucostasis. Pueden tener complicaciones en el sistema pulmonar, el sistema neurológico y otras áreas debido al alto recuento de glóbulos blancos. Dado que son más “viscosos”, se adhieren mejor a las células endoteliales y causan problemas relacionados con la agregación de glóbulos rojos en arterias y capilares. Algo relativamente poco común en la AML es un sarcoma mieloide, una presentación o masa extramedular asociada que puede ocurrir en cualquier parte del cuerpo; si se manifiesta en la piel, se denomina leucemia cutis.

22

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

AML – Prognosis • Median overall survival of about 12 months – Patients < 55 median OS has improved ~ 21 months – Patients > 55 median OS is still 6 to 8 months

• Cytogenetics – Favorable, intermediate, adverse

• Performance Status • Molecular subtypes – FLT3 mutation (30-40% of AML) – NPM1 mutation (approximately 30% of AML) – CEBPα mutation (6-15% of AML)

The prognosis of AML is relatively poor. The median overall survival is about 12 months on average. Over the past 15 to 20 years we have been improving the treatment of AML. And in younger patients the overall survival has improved somewhat to an average of 21 months. But in patients above the age of 55, the median overall survival is still grave of 6 to 8 months. And so further therapies are continued to be developed for this particular population. The maj --- In addition to age, the other major prognostic characteristics are cytogenetics or chromosomes and they are divided into three categories known as favorable, intermediate, or adverse. And we will talk about that soon in the next slide. Performance status is an important determinant of prognosis. The better performance status you have, the better you do. And finally, newer things are on the horizon, such as molecular subtypes, the so-called "FLIT3" or FLT3 mutation, which is presented in about a third of AML. Patients who have FLT3 mutations are known to have a very proliferative and aggressive disease. There is a high risk of relapse and a relatively adverse prognosis. This is a population which we would recommend getting a stem cell transplant in first remission. NPM mutation in approximately a third of AML is associated with a favorable prognosis in patients who have an NPM1 mutation but who do not have FLT3 mutation. CEBPα is also another mutation that helps associate with the prognosis.

El pronóstico de AML es relativamente malo. La mediana de supervivencia general es de unos 12 meses. En los últimos 15 a 20 años hemos mejorado su tratamiento, y en los pacientes más jóvenes la supervivencia general es de 21 meses en promedio. Sin embargo, en pacientes mayores de 55 años, la mediana de supervivencia general sigue siendo grave, de 6 a 8 meses. Por eso, continuamos desarrollando terapias para esta población. Además de la edad, los otros factores principales de pronóstico son la citogenética y los cromosomas, que se dividen en tres categorías: favorable, intermedia o adversa. Me referiré a esto en la próxima diapositiva. La capacidad funcional es un factor determinante del pronóstico. Cuanto mayor sea, tanto mejor será la expectativa. Pronto tendremos nuevas alternativas, como subtipos moleculares y la mutación FLT3, que ocurre en alrededor de un tercio de los casos de AML. Los pacientes con mutaciones FLT3 tienen una enfermedad proliferativa y agresiva. Hay un alto riesgo de recidiva y un pronóstico relativamente adverso. En esta población recomendamos un trasplante de células madre en la primera remisión. En casi un tercio de los casos de AML, la mutación NPM está asociada a un pronóstico favorable en pacientes con mutación NPM1 que no tienen la mutación FLT3. La CEBPα es otra mutación útil para el pronóstico.

23

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Cytogenetics in AML

• Favorable

t(15;17) Inv(16) t(8;21)

• Intermediate Diploid CG

+8

• Unfavorable

-5/del(5q), -7/del(7q) 11q23

So, these are the cytogenetics categories I was talking about. Favorable include three, translocation t(15;17) or APL, inversion 16, and translocation t(8;21); the last two known as core binding factor leukemias. The unfavorable are known are minus 5 or monosomy 5, monosomy 7, 11q23, among others. And the rest of them fall into the intermediate category. Complex cytogenetics or any cytogenetic karyotype having three or more abnormalities is also considered an unfavorable karyotype.

Estas son las categorías citogenéticas. Las favorables son tres: la translocación t(15;17) o APL, la inversión del cromosoma 16 y la translocación t(8;21). Las dos últimas se conocen como leucemias con factor de unión al núcleo. Las desfavorables son menos 5 o monosomía 5, monosomía 7 y 11q23, entre otras. El resto es una categoría intermedia. La citogenética compleja o cualquier cariotipo citogenético de tres o más anomalías también es un cariotipo desfavorable.

What we realized over the years is that we can divide patients --- divide patient's survival according to their cytogenetics. And so in patients who have so called "favorable" cytogenetics they have a very high median duration of remission of about 2 years with about 50% cure fraction. Whereas people with "adverse" or "bad" cytogenetics that we saw on the previous slide, have a very poor duration of remission as you see, 3 to 6 months, with a very low cure rate. And so it is important to stratify these patients by cytogenetics so that their treatments can be appropriately targeted.

A lo largo de los años, logramos dividir la supervivencia del paciente según su citogenética. Los pacientes con citogenética “favorable” tienen una remisión de duración media muy alta, de unos 2 años, con una curación de alrededor del 50%; aquellos con citogenética “mala” o “adversa” tienen una remisión muy escasa, de 3 a 6 meses, y una tasa de curación muy baja. Es importante estratificar a estos pacientes por citogenética, para dirigir sus tratamientos adecuadamente.

• Complex CG (≥ 3 abnormalities) Appelbaum FR et al, Hematology Am Soc Hematol Educ Program. 2001:62

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Cytogenetics in AML (MD Anderson Cancer Center) 1.0 Median CRD ~ 2 yrs “Cure”: ~ 50%

0.8

0.6

Favorable

Median CRD 6-24 mos. “Cure”: < 10% - 30%

0.4 Intermediate 0.2

Median CRD 3-6 mos. “Cure”: < 5% - 10%

Adverse

0.0 0

26

52

78

104

130

156

weeks

24

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Chronic Myelogenous (CML) Overview

• Rare, peak incidence at age 40 • Characterized by: – Elevated WBC with mature neutrophils – Elevated platelet count – Splenomegaly – Philadelphia chromosome positivity

• Course: – Chronic phase – Accelerated phase – Blastic phase

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Next, we move on to chronic myelogenous leukemia or CML. This is a rare disease with a peak incidence about 40. However, the prevalence of this disease is increasing because more and more people with CML are living, due to the advent of new drugs known as tyrosine kinase inhibitors. CML is characterized by elevated white blood cell count with mature neutrophils that are in the peripheral blood and the bone marrow. Sometimes the platelet count may be elevated. This is often associated with Phila --- with splenomegaly, but the hallmark of this disease is the positivity for Philadelphia chromosome or the translocation between 9 and 22. There are three phases of CML known as chronic phase, accelerating phase, and blast phase, which are treated slightly differently. Most people present in chronic phase and the blastic phase is more of an acute leukemia type of presentation which requires chemotherapy usually in addition with the tyrosine kinase inhibitor.

Ahora veremos la leucemia mieloide crónica, o CML, una enfermedad infrecuente con una incidencia máxima a los 40 años. Su prevalencia va en aumento porque cada vez más personas la padecen, debido a la disponibilidad de nuevos fármacos inhibidores de la tirosina quinasa. Se caracteriza por un aumento de glóbulos blancos, con neutrófilos maduros en la sangre periférica y la médula ósea. A veces, el recuento plaquetario aumenta. Esto suele asociarse con esplenomegalia, pero el sello distintivo de esta enfermedad es la positividad para el cromosoma Filadelfia o la translocación entre los cromosomas 9 y 22. La CML tiene tres fases: la fase crónica, la de aceleración y la fase blástica, que se tratan de manera ligeramente diferente. La mayoría de los pacientes presentan la fase crónica; la fase blástica es más bien un estado de leucemia aguda que requiere quimioterapia y un inhibidor de tirosina quinasa.

This is a Karyotype. We're looking at chromosomes 9 and 22 and the Philadelphia chromosome is often associated with a translocation of 9 and 22.

Este es un cariotipo. El cromosoma Filadelfia está a menudo asociado con una translocación de los cromosomas 9 y 22.

25

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

CML

• Philadelphia chromosome t(9;22) is hallmark of the disease • Translocation leads to bcr-abl fusion gene product

The translocation between these two chromosomes leads to the fusion gene product of BCR-ABL, but which is an abnormal gene product which is constitutively active and drives the CML process. Small molecule tyrosine kinase inhibitors such as imatinib, nilotinib, and dasatinib have revolutionized the treatment of this disease and are currently the front line of care for these diseases.

La translocación de estos cromosomas da lugar al gen de fusión BCR-ABL, un gen anormal y constitutivamente activo que impulsa el proceso de CML. Los inhibidores de la tirosina quinasa, como el imatinib, nilotinib y dasatinib, han revolucionado el tratamiento de esta enfermedad y son la primera línea de tratamiento.

Chronic lymphocytic leukemia is currently the most common adult leukemia in the western world. It has co-expression of CD5, 19, and CD23, but is CD10 negative and is very unique for most B-cell neoplasms having this, where it shares this particular phenotype only with mantle cell lymphoma. There are several stages here listed: where the highest stage in people who have thrombocytopenia; isolated anemia is known as Rai stage 3; having splenomegaly is Rai stage 2; and having lymphadenopathy alone is Rai stage 1.

En Occidente, la leucemia linfocítica crónica es la más común entre los adultos. Presenta coexpresión de CD5, 19 y 23, pero es CD10-negativa y es muy singular en la mayoría de las neoplasias de células B. Sólo comparte este fenotipo particular con el linfoma de células del manto. Aquí vemos varias etapas: la más alta aparece en personas con trombocitopenia; la presencia de anemia aislada se conoce como etapa Rai 3; con esplenomegalia, la etapa es Rai 2; si solo hay linfadenopatía, es la etapa Rai 1.

• Small molecule tyrosine kinase inhibitors have revolutionized treatment of this disease

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Chronic Lymphocytic (CLL) Overview

• This is the most common adult leukemia in the western world • Co-expression of CD5/CD19/CD23 and Sig, CD10 neg Rai stage: 0 1 2 3 4

elevated lymphocyte count lymphadenopathy splenomegaly or hepatosplenomegaly anemia thrombocytopenia

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

CLL Prognosis

• Clinical prognostic factors include stage and doubling time • Cytogenetics – – – –

13q (-) : favorable 12+ : intermediate 11q23 abnormality: unfavorable 17p (-) : unfavorable

• ZAP70 – Positive: more aggressive disease; adverse prognosis

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

CLL Prognosis

• Immunoglobulin heavy chain gene mutation – Unmutated: more aggressive disease; adverse prognosis

• CD38 positivity – Higher percentage of positivity
more aggressive

• Beta-2-microglobulin – Higher level correlates with adverse prognosis

Much like the other leukemias, we have to do all prognostic indicators. These indicators including staging of the disease that we just discovered --discussed, Rai stages 0 through 4; elevated doubling time, meaning that the lymphocyte count in the peripheral blood doubles at a quicker pace; and in cytogenetics, as we discover --- discussed previously in other leukemias, 13q in this case. 13q deletion is considered favorable, 17p deletion or 11q23 abnormality are both considered unfavorable, whereas trisomy 12 is considered an intermediate prognosis. ZAP70, which is often done by immunohistochemistry or by flow cytometry, suggests that the disease is more aggressive and carries a more adverse prognosis if it is positive in lymphocytes.

Al igual que con otros tipos de leucemia, debemos evaluar todos los indicadores de pronóstico: la estadificación de la enfermedad en etapas Rai 0 a 4; tiempos de duplicación elevados, cuando el recuento de linfocitos en la sangre periférica se duplica a un ritmo más rápido; y la citogenética, tal como en las otras leucemias, en este caso el cromosoma 13q. La eliminación de este cromosoma se considera favorable, pero la del 17p o una anomalía en 11q23 son desfavorables, en tanto que la trisomía 12 tiene un pronóstico intermedio. La presencia de ZAP70, determinada por inmunohistoquímica o citometría de flujo, sugiere que la enfermedad es más agresiva y conlleva un pronóstico más adverso si es positiva en los linfocitos.

The immunoglobulin heavy-chain gene mutation is also an important prognostic characteristic in chronic lymphocytic leukemia. In patients who are unmutated, defined as less than 3% change from the germline, the disease is usually considered more aggressive with an adverse prognosis; whereas mutated is considered or carries a better prognosis. A CD38 positivity, a higher percentage of the positivity by flow cytometry, considers --portends a more aggressive disease and beta-2microglobulin is a serum marker. The higher level often correlates with the higher bulk of disease and a more adverse prognosis.

La mutación de genes de cadena de inmunoglobulina pesada también es una característica importante de pronóstico en la leucemia linfocítica crónica. En pacientes sin esta mutación —que es un cambio inferior al 3% de la línea germinal—, la enfermedad es más agresiva, con un pronóstico adverso, pero la mutación tiene mejor pronóstico. En la positividad CD38, un mayor porcentaje de citometría de flujo señala una enfermedad más agresiva. Una mayor concentración de beta-2 microglobulina —un marcador sérico— indica una enfermedad más avanzada y un pronóstico más adverso.

27

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Myelodysplastic Syndromes (MDS)

• A heterogeneous group of malignant clonal stem cell disorders characterized by ineffective and disordered hematopoiesis and usually resulting in peripheral blood cytopenias

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Clinical Presentation of MDS

• • • • •

Half of patients are >70 years old Males = females Half of patients have no symptoms related to MDS Most common symptoms are those from anemia A few patients have symptoms of bleeding or infection • Physical findings are unusual; splenomegaly found in < 20% • Some patients present with fever

Finally, we will talk about myelodysplastic syndrome or MDS. And this is an interesting disorder because the incidence of MDS has increased significantly over the past 5 to 10 years, perhaps due to a greater recognition of this disease. It is a heterogeneous group of malignanc --- clonal stem cell disorders characterized by an ineffective and disordered hematopoiesis usually resulting in peripheral blood cytopenias. Therefore, in this particular disease, in the bone marrow, you often see a hypercellular bone marrow with lots of cellular elements, but low blood counts peripherally. There is usually not peripheral destruction but that the bone marrow precursors themselves are not able to mature sufficiently and, therefore, the hematopoiesis is ineffective. MDS is often known as pre-leukemia in many cases by many people.

Por último, hablaremos del síndrome mielodisplásico o MDS. Es un trastorno interesante, porque su incidencia ha aumentado considerablemente en los últimos 5 a 10 años, tal vez debido a un mayor grado de reconocimiento. Es un grupo heterogéneo de trastornos clonales de células madre que se caracterizan por una hematopoyesis ineficaz y desordenada, por lo general con citopenias en sangre periférica. En esta enfermedad particular, suele verse una médula ósea hipercelular pero bajos recuentos sanguíneos a nivel periférico. Normalmente no hay destrucción periférica, pero los precursores de la médula ósea no pueden madurar lo suficiente y, por lo tanto, la hematopoyesis es ineficaz. Muchas veces se considera que el MDS es una condición previa a la leucemia.

The clinical presentation of MDS: most of the patients with MDS are greater than 70 years of age. So it is a disease usually of the elderly, half of the patients usually have no symptoms and often just present to their doctor for normal blood clots and find to be anemic or slightly thrombocytopenic or leukopenic. Most common symptoms that people present for are due to anemia, due to fatigue. Some people present with bleeding or infection and physical findings are usually uncommon and splenomegaly is not very common. Some patients may present with fever due to underlying leukopenia and concomitant infection.

Analicemos la presentación clínica del MDS: la mayoría de los pacientes con MDS son mayores de 70 años, pues se manifiesta en pacientes de más edad. La mitad son asintomáticos y aunque esperan tener niveles de coagulación normales, los análisis detectan anemia, o trombocitopenia o leucopenia leves. Los síntomas más frecuentes son anemia y fatiga. Algunos presentan hemorragia o infección, y los hallazgos físicos son poco frecuentes; rara vez hay esplenomegalia. Algunos pueden tener fiebre por leucopenia subyacente e infección concomitante.

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Laboratory Evaluation of MDS

• Bone marrow – usually hypercellular, occasionally normocellular, or rarely hypocellular • There is evidence of ‘ineffective hematopoiesis’ • About half of the patients have cytogenetic abnormalities

The laboratory evaluation of MDS is listed here. Bone marrow we described earlier, the presence of ineffective hematopoiesis. About half of the patients present with some cytogenetic abnormalities that we discussed previously, but are somewhat, a little bit different in MDS and these include chromosomal deletions or extra chromosomes. And there is also dysplasia in one or more cell lines, and dysplasia is abnormal-appearing cells that do not mature into functional blood cells.

Esta es la evaluación de laboratorio del MDS. En la médula ósea, como ya dijimos, hay una hematopoyesis ineficaz. La mitad de los pacientes presentan las anormalidades citogenéticas ya mencionadas, pero son diferentes en el MDS e incluyen eliminaciones cromosómicas o cromosomas adicionales. También hay displasia en una o más líneas celulares, y células de aspecto anormal que no maduran a células sanguíneas funcionales.

So, cytogenetics changes in MDS are listed here. The most common: monosomy 7, monosomy 5, trisomy 8, 5q minus, and less common ones are also listed there. There is also an entity called treatment-related MDS, which is becoming more recognized. And this is a type of myelodysplastic syndrome that occurs in patients who have been treated previously for another malignancy with things such as alkylating agents or topo-II --topoisomerase-II inhibitors and their associated cytogenetics are listed here.

Estos son los cambios de la citogenética en el MDS. Los más comunes son monosomía 7, trisomía 8, monosomía 5 o 5q, y el resto son menos comunes. También existe el “MDS relacionado con el tratamiento”, que es cada vez más reconocido. Es un síndrome mielodisplásico en pacientes ya tratados por otras condiciones malignas con agentes alquilantes o inhibidores de la topoisomerasa II. Las citogenéticas asociadas se mencionan aquí.

• There is dysplasia of one or more cell lines – Accumulation of abnormal appearing (dysplastic) precursors that do not mature into functional blood cells

Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

Cytogenetic Changes in MDS

• Abnormal cytogenetics in 40-70% of patients • Most common: -7, 7q-, +8, -5, 5q• Less common: 20q-, iso 17, abnormal 11q • Rare: Reciprocal translocations • Treatment related MDS – Alkylating agents (-5, -7, and/or complex) 5-10 yrs – Topoisomerase II inhibitors (11q) 2-5 yrs

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Hematologic Malignancies: Diagnosis and Staging Part I: Leukemias and Myelodysplastic Syndrome

FAB Classification: FAB Classification

Median Survival (years)

Risk of Evolving to AML

RA

3.6

RARS

6.1

5%

RAEB

1

40 %

RAEB-T

0.4

50 %

CMML

1.7 Name

15 %

35 %

BM Blasts (%)

PB Blasts (%)

Ringed Sideroblasts (%)

Refractory Anemia (RA)