Leukemias and Myelodysplastic Sy

Transcripción

PowerPoint Slides
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.
1
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
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)
2
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
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.
3
Red Blood Cells (RBC)
• Packed with hemoglobin
• Carry oxygen and carbon dioxide between
the lungs and the rest of the body
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.
4
White Blood Cells (WBC)
• Different types of WBCs – specialized to fight
different infections
• Types of WBCs are:
–
–
–
–
–
neutrophils
lymphocytes
eosinophils
monocytes
basophils
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
5
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
6
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.
7
Eosinophils
• Responsible for immune reaction to parasites
• Also involved in allergic response
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.
8
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.
9
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.
10
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;
11
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.
12
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.
13
Leukemia
• A group of neoplastic diseases characterized by
abnormal proliferation of white blood cells
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.
14
Types of Leukemia
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)
15
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.
16
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
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.
17
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.
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.
18
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
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
19
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.
20
Prognostic Significance in ALL
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.
21
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
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
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
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
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
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
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
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
26
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
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
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
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.
28
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
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
29
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)
<5
≤1
< 15
Refractory Anemia with Ringed
Sideroblasts (RARS)
<5
≤1
≥ 15
Refractory Anemia with Excess Blasts
(RAEB)
5 – 20
<5
Variable
Refractory Anemia with Excess Blasts in
Transformation (RAEB-T)
21 – 30
≥5
Variable
This is the FAB Classification which had been used
previously. And this gives you an idea of the lower
risk MDS, which is refractory anemia, and refractory
anemia with ringed sideroblasts to the higher more
aggressive MDS type of categories. What is
interesting here is looking at the bone marrow blast
percentage and how this is changed with a WHO
Classification. In the past, patients who had
refractory anemia with excess blasts in
transformation were considered MDS, but in fact
anyone who has 20% or greater blasts currently in
the WHO Classification is considered AML.
Esta es la clasificación FAB ya descrita. Tenemos el
MDS de bajo riesgo, que es la anemia refractaria;
luego, la anemia refractaria con sideroblastos en
anillo; y también las categorías de MDS más
agresivas. Es interesante considerar el porcentaje
de blastos en la médula ósea y cómo difiere de la
clasificación de la OMS. Antes se consideraba que
los pacientes con anemia refractaria con exceso de
blastos en transformación tenían MDS, pero
actualmente, según la OMS, cualquier persona con
20% o más de blastos se considera con AML.
This is the current classification. The ones listed in
green here are the lower risk MDS. And as you go
down into the red, it is considered high-risk MDS
with a higher proportion of blasts in the bone
marrow and the peripheral blood as well as more
adverse cytogenetic abnormalities and more
cytopenias.
Esta es la clasificación de la OMS. Las categorías
en verde son MDS de bajo riesgo. La zona de color
rojo, se considera MDS de alto riesgo con mayor
proporción de blastos en la médula y la sangre
periférica, así como anomalías citogenéticas más
adversas, y más citopenias.
Greenberg P et al. Blood. 1997 89(6):2079
World Health Organization MDS Categories (2008)
Name
Abbrev.
Key Feature
RA
Anemia and erythroid dysplasia
Proportion of
patients (%)
10
Refractory cytopenia
with unilineage
dysplasia
RN
Neutropenia and granulocytic dysplasia
<1%
RT
Thrombocytopenia and megak. dysplasia
<1%
Refractory anemia
with ring sideroblasts
RARS
>=15% ring sideroblasts
5
5q- syndrome
Del(5q)
Isolated 5q31 deletion, anemia,
hypolobated megakaryocytes
5
Refractory cytopenia
with multilineage
dysplasia
RCMD
Multilineage dysplasia with >1 cytopenia
With or without ring sideroblasts
20
Refractory anemia
with excess blasts,
type 1
RAEB-1
5-9% blasts
20
Refractory anemia
with excess blasts,
type 2
RAEB-2
10-19% blasts; ±Auer rods
20
Unclassifiable
MDS-U
Does not fit other categories
10
Childhood MDS
RCC
Often hypocellular; pancytopenia
Rare
Swerdlow SH et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Ed, 2008 IARC
30
IPSS for MDS
Score
Variable
0
0.5
1.0
1.5
2.0
BM blasts (%)
<5
5-10
-
11-20
21-30
Karyotype
Good
Intermediate
Poor
Cytopenias
0/1
2/3
Cytopenia: Neutrophils <1,500 /µl, Hemoglobin <10 g/dl, Platelets <100,000 / µl
Karyotype Category
Good
Intermediate
Poor
Chromosomes
Normal, -Y, del(5q),
del(20q)
All others
Complex (≥ 3
abnormalities),
chromosome 5
abnormalities
Risk Group
Scores
Low
0
Intermediate – 1
0.5 – 1.0
Intermediate – 2
1.5 – 2.0
High
≥ 2.5
Greenberg P et al. Blood. 1997 89(6):2079
Hematologic Malignancies: Part I Summary
• Review the normal hematologic system
• Discuss the presentation, diagnosis and staging
for various hematologic malignancies
– Leukemia
– Lymphoma
– Multiple myeloma
This is an important tool that is currently used
clinically called the International Prognostic Scoring
System for MDS. And it gives us an idea to tell
patients about their overall prognosis and three
major characteristics are used. One is a percentage
of bone marrow blast, the second is karyotype or
cytogenetics, and the third is the number of
cytopenias. Using these three variables, we give --we give each patient a score as listed in this table.
The cytogenetics are listed here. And depending on
their – depending on their number of points they are
put into different categories, such as low risk,
intermediate 1, intermediate 2,or high risk. The
reason this is important is that the overall survival of
these patients' ranges from about 6 years in patients
with low-risk MDS all the way up to 6 months in
patients with high-risk MDS.
And finally, in conclusion, as a summary, we have
reviewed the normal hematopoietic system. We
have talked about some of the diseases and the
presentation of various hematologic malignancies
such as leukemia. In the next section, we will hear
about lymphoma, multiple myeloma. And hopefully
you have been able to distinguish myelodysplastic
syndrome from acute myeloid leukemia. Thanks
again for listening. If you have any feedback or
questions, please let us know.
Esta importante herramienta es el Sistema
Internacional de Calificación de Pronóstico para
MDS, que puede usarse clínicamente para informar
a los pacientes sobre su pronóstico general. Utiliza
tres parámetros: el porcentaje de blastos en la
médula ósea, el cariotipo o citogenética, y el
número de citopenias. Usando estas tres variables,
asignamos a cada paciente una calificación según
la tabla. La citogenética se indica aquí y, según la
cantidad de puntos, se los clasifica en diferentes
categorías, como bajo riesgo, riesgo intermedio 1,
intermedio 2, o alto riesgo. La escala de
supervivencia general oscila entre 6 años para
pacientes con MDS de bajo riesgo, y 6 meses para
pacientes con MDS de alto riesgo.
Para concluir, hagamos un resumen. Analizamos el
sistema hematopoyético normal, algunas
enfermedades y la presentación de varias
condiciones malignas hematológicas, como la
leucemia. En la siguiente sección describiremos el
linfoma y el mieloma múltiple. Esperamos que esta
información le permita distinguir entre el síndrome
mielodisplásico y la leucemia mieloide aguda.
Gracias por su atención. Si tiene alguna opinión o
pregunta, no dude en consultarnos.
• Distinguish myelodysplastic syndrome from acute
myeloid leukemia
31

Leukemias and Myelodysplastic Sy

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