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Stem Cell Transplants
English Text
Stem Cell Transplants
VideoTranscript
Professional Oncology Education
Stem Cell Transplants
Time: 28:27
Soonja Roberson
Physician Assistant
Stem Cell Transplantation
The University of Texas, MD Anderson Cancer Center
Hi, I am Soonja Roberson. I am a physician assistant at
The University of Texas MD Anderson Cancer Center in
the Department of Stem Cell Transplant and Cellular
Therapy. Today, we will be discussing stem cell
transplants.
Spanish Translation
Trasplantes de células madre
Transcripción del video
Educación Oncológica Profesional
Trasplantes de células madre
Duración: 28:27
Soonja Roberson
Asistente Médica
Trasplante de células madre
Universidad de Texas, MD Anderson Cancer Center
Hola. Soy Soonja Roberson y soy asistente médica en el
MD Anderson Cancer Center de la Universidad de Texas
en el Departamento de Trasplantes de Células Madre y
Terapia Celular. Hoy hablaremos de los trasplantes de
células madre.
Stem Cell Transplants
Soonja Roberson
Physician Assistant
Stem Cell Transplantation
1
Stem Cell Transplants
Objectives
• Upon completion of this lesson, participants will
be able to:
Upon completion of this lesson, participants will be able
to: describe the purpose and methods of stem cell
transplant; define HLA typing and identify the
differences between various kinds of matches; identify
possible complications of stem cell transplant.
Al finalizar esta lección, los participantes podrán
describir el propósito y los métodos de trasplante de
células madre, definir la tipificación de HLA e identificar
diferencias entre distintos tipos de compatibilidad y
posibles complicaciones del trasplante.
Hematopoietic stem cells are progenitor cells found in the
bone marrow. They have capacity for self-renewal and
the ability to proliferate and differentiate. These cells are
denoted by flow cytometry, by cell surface marker known
as CD34.
Las células madre hematopoyéticas son células
progenitoras de la médula ósea con capacidad de
autorrenovarse, proliferar y diferenciarse. En la
citometría de flujo se indican con el marcador de
superficie celular CD34.
– Describe the purpose and methods of stem
cell transplant
– Define HLA typing and identify the differences
between various kinds of matches
– Identify possible complications of stem cell transplant
Stem Cell Transplants
Hematopoietic Stem Cells
• Progenitor cells found in the bone marrow
– Capacity for self renewal
– Ability to proliferate and differentiate
• Denoted by flow cytometry by cell surface
marker CD34
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Stem Cell Transplants
Stem Cell Transplants
Benefits of Stem Cell Transplant
• Ability to give higher doses of chemotherapy
• Capable of transferring immune competent
cells (graft) from a normal donor to an immune
incompetent recipient (host) via peripheral blood
or marrow
This is a diagram of normal hematopoiesis. At the top,
you will see a pluripotent stem cell has the ability for
self-renewal and the ability to differentiate into both
myeloid and lymphoid cell lines. The myeloid phenotype
will give rise to red blood cells, platelets, macrophages,
eosinophils, basophils, and neutrophils. The lymphoid
cell line will give rise to T-cell lymphocytes and B-cell
lymphocytes that are responsible for antibody production.
En este diagrama de la hematopoyesis normal, la parte
superior muestra una célula madre pluripotente con
capacidad de autorrenovación y diferenciación de linaje
mieloide y linfoide. El fenotipo mieloide produce
glóbulos rojos, plaquetas, macrófagos, eosinófilos,
basófilos y neutrófilos. El linaje linfoide genera linfocitos
de células T y B, responsables de producir anticuerpos.
There are many benefits to stem cell transplant. They
give you the ability to give high doses of chemotherapy.
You also can transfer immune competent cells known as
the graft from a normal donor to an immune incompetent
recipient known as the host via peripheral blood or bone
marrow. Stem cell transplant relies heavily on a donor’s
immune system to produce a heavy graft versus tumor
effect rather than relying solely on chemotherapy alone.
El trasplante de células madre ofrece muchos beneficios,
como administrar altas dosis de quimioterapia y transferir
células inmunocompetentes o injertos de un donante sano
a un destinatario inmunitario incompetente o huésped,
utilizando sangre periférica o médula ósea. Este
trasplante depende en gran medida de que el efecto del
injerto en el sistema inmunológico del donante
predomine sobre el tumor, sin depender sólo de la
quimioterapia.
• Relies heavily on donor’s immune system to
produce graft versus tumor effect rather than
chemotherapy alone
3
Stem Cell Transplants
Types of Transplants
• Autologous – recipient's own stem cells
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Lower incidence of treatment-related mortality
Can be performed in older patients
Higher risk of relapse
Relatively low rate of long-term complications
• Allogeneic – donor derived stem cells
– Higher treatment-related mortality
– Lower risk of relapse
– Higher rate of short and long-term complications
There are several types of transplants. The first is
autologous, in which the recipient’s own stem cells are
used. In this type of setting, there is a lower incidence of
treatment-related mortality. Therefore, this treatment can
be given in patients of older age. However, the downside
is there is a higher risk of relapse and a relatively low rate
of long-term complications. In the allogeneic setting, you
use donor-derived stem cells. In this setting, there is a
higher rate of treatment-related mortality; however, a
lower risk of relapse and a higher rate of short and longterm complications. More commonly now is umbilical
cord blood, which is also easily accessible, but has the
potential of causing more infectious complications.
Hay varios tipos de trasplantes. Uno es el autólogo, que
utiliza las propias células del receptor y tiene una menor
incidencia de mortalidad relacionada con el tratamiento.
Por ello, puede usarse en pacientes de edad avanzada.
Su desventaja es un mayor riesgo de recurrencia, pero
tiene una tasa relativamente baja de complicaciones a
largo plazo. El trasplante alogénico usa células madre
derivadas de donantes. Tiene una mayor tasa de
mortalidad relacionada con el tratamiento, menor riesgo
de recurrencia y mayor tasa de complicaciones a corto y a
largo plazo. Actualmente, se utiliza mucho la sangre del
cordón umbilical, fácilmente accesible pero con más
complicaciones infecciosas.
The timing of transplant is very critical. Transplant must
be done at the maximal tumor response. Hence, patients
should either be in a complete remission or a very good
partial remission, which means greater than 50% decrease
in disease burden. The patient can have no active
infections at the time of transplant, no evidence of CNS
or leptomeningeal disease, no uncontrolled chronic
illnesses. They must have adequate organ function.
They must have an adequate performance status, meaning
they must be able to perform activities of daily living
without significant side effects. And you must have an
identified donor in the allogeneic setting, and be able to
collect an adequate number of stem cells.
El momento del trasplante es crítico, pues debe hacerse
con máxima respuesta tumoral. Los pacientes deben estar
en remisión completa o parcial buena, con más del 50%
de disminución de la carga de la enfermedad. En el
momento del trasplante, el paciente no puede tener
infecciones activas ni evidencia de enfermedad
leptomeníngea o del sistema nervioso central, ni
enfermedades crónicas no controladas. Debe tener una
función orgánica y un estado funcional adecuados, y ser
capaz de realizar actividades de la vida diaria sin mayores
efectos secundarios. En el contexto alogénico, el donante
debe estar identificado y recolectarse una cantidad
suficiente de células madre.
• Umbilical cord blood
– Easily accessible
– More infectious complications
Stem Cell Transplants
Timing of Transplant
• Maximal tumor response (complete vs.
partial remission)
• No active infections
• No active CNS or leptomeningeal disease
• No uncontrolled chronic illnesses
• Adequate organ function
• Adequate performance status
• Identified donor (allogeneic only)
• Adequate stem cell collection
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Stem Cell Transplants
Indications for Transplant
• High risk leukemias
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Induction failures
Poor risk cytogenetics
Relapsed disease
Therapy related MDS or AML
ALL – MLL gene, Philadelphia chromosome
Tyrosine-kinase resistant CML or blast crisis
Refractory CLL or transformed large cell lymphomas
Relapsed or refractory Hodgkin’s lymphoma
Relapsed non-Hodgkin’s lymphoma
Chemo-sensitive multiple myeloma
Stem Cell Transplants
Preparation for Transplant
• Chemotherapy preparative regimen
– Ablative
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Myeloid/lymphoid malignancies
Younger/healthier
Highly immunosuppressive
More risk of toxicity/less risk of relapse
– Reduced intensity or non-myelobalative
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Lymphomas/myelomas/leukemia
Heavily pretreated or prior transplant
Older
Immunosuppressive
Less toxicity/potential increased risk of rejection
There are many indications for stem cell transplant. Most
commonly transplants are done for patients with high-risk
leukemias. In that setting, those patients either have
induction failure, or who have poor risk cytogenetics,
who have relapsed disease after standard chemotherapy,
or who have treatment-related myelodysplastic syndrome,
or AML, or who have high-risk ALL, meaning they have
the MLL gene mutation or Philadelphia chromosome by
molecular or FISH testing. In addition, patients with
tyrosine-kinase resistant CML or blast crisis, refractory
CLL or transformed large B-cell lymphoma, refractory or
relapsed Hodgkin's lymphoma, relapsed Hodgkin’s
lymphoma, and chemosensitive multiple myeloma.
Hay muchas indicaciones para los trasplantes de células
madre. Las más comunes son leucemias de alto riesgo en
pacientes con insuficiencia inductiva, escaso riesgo
citogenético, recurrencia luego de quimioterapia estándar,
síndrome mielodisplásico relacionado con el tratamiento,
leucemia mieoloide aguda, riesgo por mutación del gen
de leucemia de linaje mixto, o cromosoma Filadelfia por
análisis molecular o hibridación fluorescente in situ.
Se recomienda para la leucemia mieloide crónica
resistente a la tirosina quinasa o crisis blástica, el
carcinoma pulmonar de Lewis resistente, el linfoma de
células B grandes transformado, el linfoma de Hodgkin
resistente o recurrente, y el mieloma múltiple
quimiosensible.
There are several types of preparative regimens for
indication for transplant. This means the chemotherapy
that the patient is receiving prior to their stem cell
collection. The chemotherapy preparative regimen can
either be ablative or reduced intensity or nonmyeloablative. Ablative means that the bone marrow is
completely ablated by the chemotherapy.
This is
typically used in myeloid and lymphoid malignancies and
is reserved for younger and healthier patients because the
treatment is much stronger. The therapy is very highly
immunosuppressive. Therefore, there is more risk of
toxicity, but, hence, less risk of relapse. In the reduced
intensity setting, this is typically reserved for patients
with lymphomas, myelomas in older patients with
leukemia. Most of these patients are heavily pre-treated
or have had a prior transplant. Most of these patients are
also older. However, reduced intensity also causes some
immunosuppression. There is, however, less toxicity,
again because the therapy is less high dose and because
the therapy is less high dose there is a potential risk of
rejection.
Para el trasplante, hay varios regímenes de preparación,
es decir, la quimioterapia que recibe el paciente antes de
la recolección. El régimen de preparación de
quimioterapia puede ser ablativo, de intensidad reducida
o no mieloablativo. “Ablativo” significa que la médula
ósea es completamente anulada por la quimioterapia. Este
tratamiento suele usarse en neoplasias linfoides y
mieloides, y se reserva para pacientes más jóvenes y
saludables, ya que es más intenso. La terapia es altamente
inmunosupresora, con un mayor riesgo de toxicidad y
menor riesgo de recurrencia. El tratamiento de intensidad
reducida es para linfomas o mielomas en pacientes
mayores con leucemia. Casi todos ya habrán sido
extensamente tratados y habrán recibido un trasplante
previo, y tendrán mayor edad. La intensidad reducida
también causa cierta inmunosupresión; no obstante, hay
menos toxicidad porque la terapia no es a dosis tan altas y
por eso existe un riesgo de rechazo.
5
Let’s first discuss autologous transplant in detail.
Primero describiremos el trasplante autólogo.
In the autologous setting, we use the patient’s own stem
cells. This can be collected either via peripheral blood or
bone marrow stem cells collected prior to the high-dose
chemotherapy that will be given. This type of treatment
is indicated in chemosensitive, recurrent Hodgkin’s
lymphoma, chemosensitive, low-grade, or intermediate
grade lymphomas, and multiple myeloma.
En este trasplante utilizamos las propias células madre
del paciente. Pueden recolectarse utilizando sangre
periférica o médula ósea antes de administrar altas dosis
de quimioterapia. Este tratamiento se indica en pacientes
con linfoma de Hodgkin recurrente y quimiosensible,
linfomas de grado bajo o intermedio, y mieloma múltiple.
Stem Cell Transplants
Autologous Transplant
Stem Cell Transplants
Autologous Transplant
• Uses patient’s own stem cells for transplant
• Peripheral blood or bone marrow stem cells
collected prior to high dose treatment
• Indicated for:
– Chemosensitive recurrent Hodgkin’s lymphoma
– Chemosensitive low grade or intermediate
grade lymphomas
– Multiple myeloma
6
Stem Cell Transplants
Stem Cell Collection
• Completed before high dose regimen given
• Collected either via peripheral blood or bone marrow harvest
• Collected after bone marrow stimulation either with growth
factors or growth factors plus chemotherapy
– Chemotherapy plus growth factors usually yields higher CD34
count than growth factors alone in heavily pretreated patients
• Stems cells are cryopreserved until time of transplant
• Adequate cell dose
– Autologous transplant > 2 million CD34+/kg of recipient's weight
– Allogeneic transplant > 4 million CD34+/kg of recipient's weight
Stem Cell Transplants
Autologous Transplant Process
• Collection of stem cells
• Administration of high dose chemotherapy given over
week’s time
• Within 24-48 hours after completion of
chemotherapy, stems cells are infused via central
venous access
As stated before, the stem cell collection is done prior to
the high-dose regimen being given. The cells again are
collected via either peripheral blood or bone marrow
harvest. If the cells are collected via peripheral blood, the
bone marrow needs to be stimulated by a growth factor
known as Neupogen®. In some cases, we also give
chemotherapy in addition to the growth factor. By giving
chemotherapy in addition to the growth factor,
particularly in patients with lymphoma who have been
heavily pretreated, it helps yield a higher CD34 count and
hence increases the number of stem cells collected
pretransplant. Once the cells are collected, they are
cryopreserved until the time of transplant. An adequate
stem cell dose in the autologous setting is greater than 2
million CD34 cells/kg of the recipient’s weight. In the
allogeneic setting, the cell dose is greater than 4 million
CD34 cells/kg of the recipient’s weight.
The autologous transplant process is very simple. First,
the cells are collected as discussed before. The high-dose
chemotherapy is given over a week’s time. Within 24-48
hours after the completion of the chemotherapy, the stem
cells are infused like a blood transfusion via central
venous catheter. It takes about 2 to 3 weeks for the
peripheral blood counts to recover following the highdose chemotherapy. During this time, patients are
susceptible to infection and, therefore, prophylactic
antibiotics are given as well as growth factors during
their peri-transplant and post-transplant course.
Ya mencioné que la recolección de células madre se
realiza antes de un régimen de altas dosis de
quimioterapia. Las células se toman de la sangre
periférica o del cultivo de médula ósea. Si se recolectan
de la sangre periférica, la médula debe estimularse con el
factor de crecimiento Neupogen®. A veces también
administramos quimioterapia, en cuyo caso, sobre todo
en pacientes con linfoma extensamente tratados, ayuda a
aumentar el recuento de CD34 y la cantidad de células
madre recolectadas antes del trasplante. Una vez que
estas se recolectan, son criopreservadas hasta el
trasplante. En el contexto autólogo, una dosis adecuada
de células madre debe ser superior a 2 millones de células
CD34/kg de peso del receptor. En el alogénico, la dosis
debe superar los 4 millones de células CD34/kg.
El trasplante autólogo es muy simple. Primero, las células
se recolectan como ya se explicó. La quimioterapia de
alta dosis se administra por una semana. Luego de 24 a
48 horas de finalizada, las células madre se infunden por
transfusión de sangre a través de un catéter venoso
central. Tras la administración de estas altas dosis, el
paciente recupera los recuentos de sangre periférica en 2
a 3 semanas. Durante ese tiempo, es susceptible a
infecciones y se le administran antibióticos profilácticos
y factor de crecimiento en los períodos peritrasplante y
postrasplante.
• Recovery of peripheral blood cells occurs within
2-3 weeks
• Prophylactic antibiotics and growth factors support
given as needed peri- and post-transplant
7
In contrast, allogeneic transplant…
Por el contrario, el trasplante alogénico…
…relies heavily on stem cells from a genetically HLA
compatible donor. This donor can be either from the
family, known as related, or from the National Marrow
Donor Program, or the unrelated donor registry. These
cells also can be collected via peripheral blood or bone
marrow. Once again, chemotherapy is given prior to the
stem cell infusion. In this setting, however, patients are
given anti-rejection or immunosuppression medication
prior to the stem cell infusion and are continued on the
immunosuppressive medication up to 6 months after the
stem cell infusion.
… depende en gran medida de las células madre de un
donante genéticamente compatible con antígenos de
leucocitos humanos. Puede ser un familiar o pertenecer al
Programa Nacional de Donantes de Médula Ósea o al
registro de donantes no relacionados. Las células también
pueden recolectarse de la sangre periférica o de la
médula. La quimioterapia se administra antes de infundir
células madre, pero los pacientes reciben medicación
antirrechazo o inmunosupresora antes de la infusión y
continúan con medicación durante 6 meses.
Stem Cell Transplants
Allogeneic Transplant
Stem Cell Transplants
Allogeneic Transplant
• Treatment relies on collected stem cells
from a genetically (HLA) compatible donor
• Donor can be either related or unrelated
• Stem cells collected via peripheral blood
or bone marrow
• Chemotherapy administered prior to stem
cell infusion
• Anti-rejection/immunosuppression given
prior to stem cell infusion and continued up
to 6 months post transplantation
8
Stem Cell Transplants
Allogeneic Transplant
• Benefits
– Graft versus tumor effect
– Potential lower relapse rate
– Potential improvement in overall survival
There are many benefits to an allogeneic transplant.
First, is an allogeneic transplant provides a strong graft
versus tumor effect and hence lowers the rate of relapse
for the patient. In turn, this also increases the overall
survival for the patient. However, there are many
complications that can be fatal in the post-transplant
setting. This includes graft versus host disease, which we
will discuss later, infectious complications, and graft
rejection or graft failure.
El trasplante alogénico ofrece muchos beneficios, pues
provee un fuerte efecto del injerto frente al tumor y
reduce la tasa de recurrencia en el paciente, lo que
aumenta la supervivencia general; sin embargo, hay
muchas complicaciones que pueden resultar fatales en la
etapa postrasplante, como la enfermedad de injerto contra
huésped —que veremos más adelante—, complicaciones
infecciosas y rechazo o fallo del injerto.
HLA donors require a stringent HLA typing. HLA stands
for human leukocyte antigen. It is DNA-based typing
found on chromosome 6. We look at the major
histocompatibility class I and II. Class I is denoted by the
loci A, B, and C. Class II is denoted by the loci DR, DQ,
and DP. Each individual inherits one set from each
parent. And hence for a perfect match we would like to
have a perfect 10/10 match. If we look at the primary
three loci that causes the most increase in graft versus
host disease: A, B, and DR, the minimum number of
match you must have to have a successful transplant is 5
of 6, meaning you can have one mismatch in either one of
those loci. If you look out further to class II, including
DQ, the minimum match you can have is 10, and so on
and so forth. This type of blood test is done on peripheral
blood and takes about 2 weeks to have the final results.
Los donantes de antígenos de leucocitos humanos, o
HLA, requieren una estricta tipificación por el ADN del
cromosoma 6. Analizamos entonces el complejo mayor
de histocompatibilidad de las clases I y II. La clase I está
representada por los locus A, B y C; la II, por los locus
DR, DQ y DP. Toda persona hereda un conjunto de cada
progenitor. Para una combinación perfecta, debemos
tener una compatibilidad 10/10. Para los tres locus
primarios que provocan el mayor aumento de la
enfermedad de injerto contra huésped —A, B y DR—, la
compatibilidad mínima para que el trasplante sea exitoso
es 5 de 6, es decir, una incompatibilidad en cualquiera de
los locus. Si observamos más detenidamente la clase II,
incluido el locus DQ, la compatibilidad mínima es 10, y
así sucesivamente. Este tipo de análisis se realiza en
sangre periférica y demora unas 2 semanas.
• Risks/complications
– Graft versus host disease (GVHD)
– Infectious complications
– Graft rejection/failure
Stem Cell Transplants
Allogeneic Donor
• Requires HLA (human leukocyte antigen) testing
– DNA based
– Divided into major histocompatibility (MHC) class I
and class II
• Class I is denoted by the A, B, C loci
• Class II is denoted by DR, DQ, DP loci
• Minimum of 5 out of 6 match (A,B, DR)
• Minimum 9 out 10 match (A,B,C,DR, DQ)
• Minimum 13 out of 14 match (A, B, C, DR, DQ, DP)
• Performed on peripheral blood sample
9
Stem Cell Transplants
Allogeneic Donor
• Health status
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Age
Past medical history
Infectious disease testing
CMV serology
Pregnancy history
Physical examination
Stem Cell Transplants
When assessing the donor, we look at their health status.
We would like younger donors. We assess their past
medical history. We look at infectious disease testing
including hepatitis and HIV serologies. We look at CMV
serology, pregnancy history, and the donor takes a
thorough physical examination.
Al evaluar a un donante, consideramos su estado de
salud. Preferimos los donantes más jóvenes. Examinamos
su historial médico y los análisis de enfermedades
infecciosas, como los resultados serológicos de hepatitis,
VIH y citomegalovirus, y los antecedentes de embarazo;
y realizamos un examen físico completo.
There are many types of stem cell sources: peripheral
blood, bone marrow, and umbilical cord blood.
Hay varias fuentes de células madre: la sangre periférica,
la médula ósea y la sangre de cordón umbilical.
Stem Cell Sources
• Peripheral blood
• Bone marrow
• Umbilical cord blood
10
Stem Cell Transplants
Stem Cell Sources
• Peripheral blood
• Bone marrow
– Easily collected
– Faster engraftment
– Potential increased
risk of graft versus
host disease
– Collected under general
anesthesia
– Slower engraftment
of platelets
– Potential decreased risk of
graft versus host disease
Stem Cell Transplants
Umbilical Cord Blood
• Advantages
– Easily available via cord
blood bank
– Non-invasive collection
– Minority targeted
– Less stringent donor HLA
matching
– Potential decreased risk
of graft versus host
• Disadvantages
– Lower cell dose
• Slower engraftment
• More infectious
complications
• Increased risk of
graft failure
Peripheral blood is easily collected. It is collected via
venous catheter in the vein after stimulation by
Neupogen because these cells are in the peripheral
blood and are more susceptible and have seen antigen
before, therefore, making them more immune competent,
once given to the patient, the patient tends to engraft
quicker, which means their counts tend to recover quicker
after infusion. Because these cells are more immune
competent and have been exposed to antigen, there is an
increased risk of graft versus host disease for the patient.
Unlike peripheral blood, in the bone marrow setting,
these cells are collected via general anesthesia in the
operating room. These cells are more naïve, they have
not been circulating in the peripheral blood, and,
therefore, have not seen antigen and, therefore, once
given to the patient, the patient’s counts are slow to
recover. This increases their risk of infection and
bleeding complications post-transplant. But because
these cells are naïve it decreases the patient’s risk of graft
versus host disease.
The third type of stem cell source is umbilical cord blood.
They are many advantages to umbilical cord blood. First,
cord blood units are found throughout the world in
multiple banks throughout the United States and the
world in general. These cells are collected noninvasively
after the baby is born by an OB/GYN. Cord blood is
minority targeted, generally selected for patients of
African-American, or Asian origin. Because these cells
are very immune-incompetent and very naïve, there is
less DNA --- there is less stringent donor HLA typing,
and these cells tend to cause less graft versus host
disease. The disadvantage to umbilical cord blood is that
these cell doses are small, and, therefore, once given to
the patients it takes their counts many more weeks to
recover and hence there is slower engraftment. Because
the counts are slow to recover, patients are at more risk
for infectious complications and of risk of actually
La sangre periférica se recolecta fácilmente insertando un
catéter venoso después de estimular con Neupogen®,
porque estas células son más susceptibles. Ya han estado
en contacto con antígenos y hay que hacerlas más
inmunocompetentes al administrarlas al paciente; así, el
injerto se adapta más rápidamente y los recuentos se
recuperan más velozmente tras la infusión. Como son
más inmunocompetentes y han sido expuestas al
antígeno, hay un mayor riesgo de enfermedad de injerto
contra huésped. A diferencia de la sangre periférica, las
células medulares se recolectan con anestesia general en
la sala de operaciones. Son menos reactivas, pues no han
circulado en sangre periférica y no han tenido contacto
con el antígeno. Una vez administradas, la recuperación
de recuentos del paciente es más lenta, lo que aumenta el
riesgo de complicaciones infecciosas y sangrado
postrasplante. Como son menos reactivas, el riesgo de
desarrollar dicha enfermedad es menor.
El tercer tipo de fuente es la sangre de cordón umbilical,
cuyas ventajas son numerosas. Existen unidades
hemáticas de cordón umbilical en varios bancos de los
Estados Unidos y, en general, en todo el mundo. Las
células son recolectadas por el obstetra o ginecólogo de
manera no invasiva después del nacimiento del bebé.
La sangre umbilical se utiliza mucho en pacientes de
minorías étnicas, generalmente de origen afroamericano o
asiático. Como son muy inmunoincompetentes y poco
reactivas, hay menos tipificación estricta de HLA y
tienden a causar menos enfermedad de injerto contra
huésped. La desventaja de esta sangre es que las células
son escasas y, una vez que se administran, la
recuperación de recuentos demora muchas semanas y el
injerto tarda más en adaptarse. Con una recuperación de
recuentos más lenta, los pacientes corren un mayor riesgo
de complicaciones infecciosas y rechazo del injerto.
11
rejecting their graft.
In the post-transplant setting…
En el período postrasplante…
…there are multiple complications. Obviously, these
include infections due to the severe immunocompromised
patient, graft versus host disease, organ damage from the
chemotherapy, potential risk of graft failure or rejection,
and also relapse is a major concern.
… hay muchas complicaciones, como infecciones por
una severa inmunodepresión del paciente, enfermedad de
injerto contra huésped, daños a órganos por
quimioterapia, riesgo de fallo o rechazo del injerto, y un
grave potencial de recurrencia.
Stem Cell Transplants
Post-transplant Complications
Stem Cell Transplants
PostPost-transplant Complications
•
•
•
•
•
Infections
Graft versus host disease
Organ damage
Graft failure/rejection
Relapse
12
Stem Cell Transplants
Infections
• Major cause of mortality after transplant
• Early (first 100 days)
– Viruses
• Herpes simplex (HSV), Cytomegalovirus (CMV), Varicella
zoster virus (VZV)
– Bacterial
• Late
In the infection setting, infections can be the major cause
of mortality after transplant. In their early post-transplant
course, meaning within their first 100 days, viruses are
the most common infections that affect our patients.
These include herpes simplex virus, cytomegalovirus, and
varicella zoster. Also, bacterial infections are still
common in the peri- and post-transplant course. In the
late post-transplant course, meaning beyond day 100,
Epstein Barr virus is the common viral complication and
also fungal infections, particularly aspergillus, becomes a
problem.
Luego del trasplante, las infecciones pueden ser la causa
principal de mortalidad. En los primeros 100 días del
período inicial postrasplante, las más comunes en
nuestros pacientes son los virus, como el del herpes
simple, el citomegalovirus y la varicela zoster. Las
infecciones bacterianas siguen siendo comunes en los
períodos peritrasplante y postrasplante. En el período
tardío postrasplante, pasados los 100 días, el virus de
Epstein Barr es la complicación viral más común, y las
infecciones micóticas, especialmente las de Aspergillus,
también son problemáticas.
To prevent these problems, the patients are given
prophylactic antibiotics up to six months post-transplant,
to cover both viruses, bacterial, and fungal infections. In
addition, we also prophylax for pneumocystis infection.
There is also stringent surveillance for CMV reactivation.
And some patients are also prophylaxed against
cytomegalovirus, particularly if they have had previous
CMV infection.
Para evitar esto, administramos antibióticos profilácticos
hasta seis meses después del trasplante para prevenir
infecciones virales, bacterianas y micóticas, y se hace
profilaxis contra la infección neumocística. Hay una
estricta supervisión de la reactivación del
citomegalovirus, y algunos pacientes reciben tratamiento
profiláctico adicional contra este virus, sobre todo si ya
han estado infectados.
– Viruses
• Epstein-Barr (EBV), Cytomegalovirus (CMV)
– Bacterial
– Fungus
Stem Cell Transplants
Prophylaxis
• Up until 6 months
–
–
–
–
–
Antiviral
Antibacterial
Antifungal
Pneumocystis carinii
CMV surveillance for activation vs. prophylaxis
13
Stem Cell Transplants
Graft Versus Host Disease (GVHD)
• What is it?
– Inflammatory response mediated by donor cell’s (graft)
reactivity to host cells characterized by
• antigen presentation and T cell recognition
• cytokine release
• tissue damage
Linked to HLA compatibility
Develops in > 50% patients
Acute or chronic
Can be life threatening if uncontrolled or refractory
to front-line treatment
• Prophylaxis given up to 6 months post transplant
•
•
•
•
Graft versus host disease, as discussed before is a major
complication post-transplant. So what is graft versus host
disease? It is an inflammatory response mediated by the
donor cells, which is the graft reactivity to the host cells
characterized by antigen presentation and T-cell
recognition. There is a strong cytokine release due to
damage of the patient’s tissue from the chemotherapy.
This cytokine release leads to an inflammatory response
that causes tissue damage for the patient. Graft versus
host disease is highly linked to the HLA compatibility.
Hence, the more incompatibility you have, the more risk
of graft versus host disease. Graft versus host disease, or
GVHD, occurs in approximately 50% of our patients
despite being prophylaxed against it. We describe
GVHD as either acute or chronic, depending on the time
at which it occurs after the transplant. In the acute
setting, this occurs within the first 100 days after the stem
cells are infused, and in the chronic setting, this occurs
after the first 100 days. If graft versus host disease is not
controlled or treated properly, it can be life threatening.
And again, as stated before, we do give prophylaxis but,
once patients develop the GVHD, they must be treated
aggressively.
Como mencionamos anteriormente, la enfermedad de
injerto contra huésped es una importante complicación en
el período postrasplante. ¿Qué es esta enfermedad?
Es una respuesta inflamatoria mediada por las células del
donante como una reacción del injerto a las células
huésped, caracterizada por la presentación del antígeno y
el reconocimiento de las células T. Hay una gran
liberación de citoquinas por los daños de la quimioterapia
a los tejidos, lo que conduce a una respuesta inflamatoria
perjudicial. Esta enfermedad está muy vinculada a la
compatibilidad HLA. Cuanta más incompatibilidad hay,
tanto mayor es el riesgo. A pesar del tratamiento
profiláctico, la enfermedad de injerto contra huésped, o
GVDH, ocurre en un 50% de nuestros pacientes.
La describimos como aguda o crónica, según el momento
en que ocurra luego del trasplante. En la fase aguda,
ocurre dentro de los primeros 100 días de infundir células
madre; en la crónica, demora más tiempo. Si no se
controla o no se trata adecuadamente, puede ser mortal.
Ya mencioné que utilizamos profilaxis pero, una vez que
un paciente la desarrolla, debe ser tratado agresivamente.
14
Stem Cell Transplants
GVHD Risk Factors
• Age of recipient
– Older > younger
• HLA match of donor to recipient
– Mismatch > perfect match
• Stem cell source
– Peripheral blood > bone marrow
• Gender mismatching
– Female --> male recipient > male --> female recipient
• Intensity of preparative regimen
– Ablative > reduced intensity
• GVHD prophylaxis
Stem Cell Transplants
GVHD Manifestations
• Skin
– Erythematous, maculopapular rash
– Hyperpigmentation
– Scleroderma
• Gastrointestinal tract
– Oral pain/sensitivity, decreased saliva, abdominal
cramping, nausea, vomiting, diarrhea
•
•
•
•
Liver – hepatitis, elevated bilirubin
Lung – shortness of breath
Eyes – dry, red, irritated eyes
Fascia – joint stiffness, swelling, pain
There are many risks for graft versus host disease. First,
age is major risk, the older the patient the greater the risk.
HLA matching, the more mismatches you have, the more
risk of GVHD you may have. The stem cells source,
peripheral blood causing more graft versus host disease
than bone marrow, again due to the fact that peripheral
blood is more immune competent than bone marrow.
Gender mismatching, we typically like to have a female
donor give to another female donor because females who
have had children produce more antibodies and this
produces more risk of graft versus host disease when
given to a male recipient. The intensity of the preparative
regimen, the ablative regimens tend to cause more graft
versus host disease because there is more tissue damage
from this strong chemotherapy, which can incite graft
versus host disease and the type of prophylaxis that is
given to the patients.
There are many kinds of GVHD manifestations. The skin
is a common organ system affected by graft versus host
disease. In the acute setting, the typical presentation can
be a fine maculopapular rash that is erythematous and it
may or may not be pruritic. In the chronic setting, we see
more hyperpigmentation and scleroderma, much like
autoimmune scleroderma. In the GI tract, GVHD can
affect anywhere from the mouth to the rectum. Oral
symptoms can include sensitivity, poor appetite, [and]
decreased saliva.
You can also have abdominal
cramping, nausea, vomiting, diarrhea, weight loss, and
malabsorption. GVHD also affects other organ systems
including the liver, which causes hepatitis and jaundice.
Pulmonary system is affected, which results in shortness
of breath. Eyes can be affected, which can cause dry eye
syndrome, also dry, irritated eyes. And also the fascia
can be affected, which leads to joint stiffness, pain, and
swelling.
Existen muchos riesgos de desarrollarla. La edad es un
riesgo importante: a mayor edad, mayor riesgo. Otro
factor es la compatibilidad HLA: a menor coincidencia o
más incompatibilidad, tanto mayor es el riesgo. Y la
fuente de células madre, pues la sangre periférica causa
más instancias que la médula ósea por ser más
inmunocompetente que esta. Otro factor es el sexo no
coincidente: en general, preferimos una donante femenina
para otra donante femenina, ya que las mujeres que han
tenido hijos producen más anticuerpos y eso causa mayor
riesgo de enfermedad en destinatarios masculinos.
Además, tenemos la intensidad del régimen de
preparación: los regímenes ablativos causan más
instancias, porque hay más daños tisulares provocados
por una quimioterapia intensa, lo que puede estimular la
enfermedad. Por último, tenemos el tipo de profilaxis
utilizada.
Hay numerosas manifestaciones de GVDH. La piel es un
sistema orgánico comúnmente afectado por ella. En la
fase aguda, la típica presentación suele ser una erupción
maculopapular fina y eritematosa, con o sin prurito. En la
fase crónica, hay más hiperpigmentación y esclerodermia,
muy similar a la esclerodermia autoinmune. En el tracto
gastrointestinal, la enfermedad puede afectar desde la
boca hasta el recto. Los síntomas orales son sensibilidad,
falta de apetito y disminución de la saliva. Puede haber
cólicos, náuseas, vómitos, diarrea, pérdida de peso y mala
absorción. La GVDH también afecta otros órganos, como
el hígado, causando hepatitis o ictericia. Asimismo, el
sistema pulmonar puede verse afectado por falta de
aliento. En los ojos, provoca el síndrome del ojo seco y
ojos secos e irritados. Puede afectar la fascia, lo que
conduce a rigidez, dolor e inflamación articular.
15
Stem Cell Transplants
Cutaneous GVHD
Stem Cell Transplants
Hyperacute Cutaneous GVHD
This is a picture of acute cutaneous graft versus host
disease evidenced by erythema in a macular rash that
may or may not be pruritic.
Este es un cuadro cutáneo agudo de la enfermedad,
evidenciada por eritema en una erupción macular, que
puede o no ser pruriginosa.
This is a picture of hyperacute cutaneous graft versus
host disease. Hyperacute meaning the GVHD has
occurred within the first 30 days after stem cell infusion.
This is a very angry, red, painful rash the patient has
experienced after the stem cell infusion
Esta es una reacción cutánea hiperaguda de la
enfermedad, la cual se manifiesta dentro de los primeros
30 días tras la infusión de células madre. Es una erupción
intensa, roja y dolorosa que el paciente experimenta
después de la infusión.
16
Stem Cell Transplants
Ocular GVHD
Stem Cell Transplants
Oral GVHD
This is an example of ocular graft versus host disease
where the patient’s eye is very red, irritated, and injected
[speaker intended to say “infected”].
Esta es una manifestación ocular en la que el ojo del
paciente está muy enrojecido, irritado e infectado.
Oral graft versus host disease manifested by pain [and]
redness in the oral mucosa. There are also can be
changes on the hard palate and tongue.
La enfermedad oral se manifiesta por dolor y
enrojecimiento de la mucosa oral. Puede haber cambios
en el paladar duro y la lengua.
17
Stem Cell Transplants
Diagnosis
• Clinical
• Pathology
– Biopsy of the affected site and clinical presentation
• Diagnostic/radiographic data
The clinical diagnosis of graft versus host disease can be
made by the history and physical examination, although
biopsy to get a pathological diagnosis is also essential.
Most commonly, we can easily do skin, liver, and bowel
biopsies. For the lung, we typically rely on pulmonary
function testing looking at residual volume and forced
vital capacity. And we also use high-resolution CT
scanning to assess any abnormalities within the lung
parenchyma.
Para el diagnóstico clínico, puede analizarse el historial y
efectuarse un examen físico, pero es esencial hacer una
biopsia de diagnóstico patológico. Podemos realizar más
fácilmente biopsias de la piel, el hígado y el intestino.
Para los pulmones, solemos basarnos en pruebas de
función pulmonar por volumen residual y capacidad vital
forzada. La tomografía de alta resolución permite evaluar
anomalías del parénquima pulmonar.
Treatment for graft versus host disease can either be
systemic or localized depending on the extensiveness of
the disease. If there is more than one organ system
affected, high-dose steroids are given. This is given in the
form of Medrol, at 1 to 2 mg/kg of the patient’s weight.
Once the patient starts to respond in their clinical
symptoms then the Medrol is tapered. There is about a
50% response rate when steroids are given up front. In
addition to steroids, however, immunosuppression must
also be given in the form of tacrolimus. Blood levels of
tacrolimus must be monitored closely. Supratherapeutic
levels can cause both neuro and renal toxicity.
Subtherapeutic levels can cause inappropriate treatment
and inappropriate response of the clinical symptoms. In
addition to oral medications, a procedure called
photophoresis can also be utilized for both skin and GI
symptoms. In this setting, a patient is taken to the
apheresis unit, their stem cells are pulled out like dialysis.
The cells are injected with psoralen, which makes them
sensitive to UV light. The cells are then zapped with UV
light and then re-injected into the patient. In this setting,
El tratamiento de la enfermedad de injerto contra huésped
puede ser sistémico o localizado, según la extensión. Si
hay más de un sistema de órganos afectado, se
administran altas dosis de esteroides en forma de
Medrol® (1 a 2 mg/kg de peso del paciente). Una vez que
este comienza a responder en su sintomatología clínica,
reducimos gradualmente el Medrol®. Si los esteroides se
administran inicialmente, la tasa de respuesta es de un
50%; sin embargo, además de los esteroides, la
inmunosupresión también debe administrarse en forma de
tacrolimus. Sus niveles en sangre deben monitorearse
atentamente. Los niveles supraterapéuticos pueden causar
toxicidad renal y neurológica; los subterapéuticos, un
tratamiento y una respuesta inadecuados de los síntomas.
Además de medicamentos orales, también puede
utilizarse fotoforesis, tanto para la piel como para los
síntomas gastrointestinales. El paciente es llevado a la
unidad de aféresis. Sus células madre son extraídas como
en la diálisis y se les inyectan psoralenos, que las hace
sensibles a la luz UV. Luego de iluminarlas, son
reinyectadas. El objetivo es suspender los esteroides lo
– Lung involvement can be assessed by
pulmonary function tests and high resolution
computed tomography
Stem Cell Transplants
GVHD Treatment
• Systemic involvement
– Methylprednisolone @ 1-2 mg/kg initially then taper
• ~50% response rate
– Immunosuppression: tacrolimus
– Photopheresis
• Localized involvement
– Eyes - punctal plugs, steroid eye drops
– Mouth - dexamethasone mouth wash
– Skin - topical steroid cream, topical moisturizers
18
Stem Cell Transplants
GVHD Treatment
• Second line agents
–
–
–
–
–
Mycophenolate mofetil
Infliximab
Cyclosporine
Anti-thymoglobulin
~10% long term survival
your goal is to try to get the patient off of the steroids as
soon as possible. Photopheresis is given over several
months, two to three times per week, until the symptoms
have subsided. For localized treatment, particularly the
eyes, mouth, and skin, it is easy to use either eye drops or
mouthwash or topical creams.
In the event that steroids are not successful, there are
second-line agents that patients can --- that can be used
for patients. This includes mycophenolate mofetil also
known as CellCept®, infliximab, which is mostly used for
the GI tract, cyclosporine, and anti-thymoglobulin. All
these regimens are successful as a second-line agent, but
if patients do not respond to these second-line agents
there is about 10% long-term survival.
antes posible. La fotoforesis se administra durante varios
meses, de dos a tres veces por semana, hasta eliminar los
síntomas. Para un tratamiento localizado, particularmente
en ojos, boca y piel, es más fácil utilizar gotas oculares,
enjuague bucal o cremas tópicas.
Si los esteroides no tienen éxito, hay una segunda línea
de agentes, tales como el mofetil micofenolato, también
conocido como CellCept®; infliximab, que se utiliza
mucho para tratar el tracto gastrointestinal; ciclosporina y
antitimoglobulina. Todos estos regímenes son adecuados
como agentes de segunda línea, pero si el paciente no
responde a estos fármacos, la supervivencia a largo plazo
es del 10%.
19
Stem Cell Transplants
Goal of GVHD Treatment
• Suppress immune reaction without suppressing graft
– Follow tacrolimus, cyclosporine level
• Improve quality of life
• Prevent superimposed infections
• Prevent secondary complications from high
dose steroids
– Diabetes
– Avascular necrosis
– Osteopenia
The goal of graft versus host disease treatment is to,
number one; suppress the immune system without
suppressing the graft. So, if a patient has a major flare of
graft versus host disease, you have to get control of the
immune response of the graft cells. You want to suppress
the cells overactiveness, but you do not want to suppress
the cells too much such that the patient may relapse. You
need to follow the tacrolimus levels again because
supratherapeutic or subtherapeutic levels can be
detrimental. You also want to improve the patient’s
quality of life. Sometimes, in some cases, patients have
severe nausea, vomiting, weight loss, cachexia, bad skin
rash, bad mouth pain, and so you want to control the
symptoms, either again with systemic treatment or
localized treatment. Because the patients will be
immunocompromised with the immunosuppressive
medication, patients must be prophylaxed against
[speaker intended to say, “with”] antibiotics. Once again,
you want to try to prevent or decrease the incidence of
superimposed infections.
You also would like to
decrease the incidence of secondary complications from
the high-dose steroids, namely diabetes, avascular
necrosis of the hips or shoulders, and also osteopenia, and
osteoporosis.
El objetivo del tratamiento de esta enfermedad es, en
primer lugar, suprimir el sistema inmunológico y no el
injerto. Si un paciente tiene un brote importante, debemos
controlar la respuesta inmunológica de las células
injertadas. Se debe suprimir su hiperactividad, pero no
demasiado como para inducir una recurrencia. Se deben
controlar los niveles de tacrolimus, ya que los niveles
supraterapéuticos o subterapéuticos pueden ser
perjudiciales. También queremos mejorar la calidad de
vida del paciente. A veces, los pacientes experimentan
náuseas intensas, vómitos, pérdida de peso, caquexia,
erupciones dérmicas graves o dolor bucal intenso, que
podemos controlar con tratamientos sistémicos o
localizados. Como están inmunocomprometidos por la
medicación inmunosupresora, se les debe administrar
profilaxis antibiótica para prevenir o disminuir la
incidencia de infecciones superpuestas. También es
deseable disminuir la incidencia de las complicaciones
secundarias derivadas de las altas dosis de esteroides,
tales como diabetes, necrosis avascular de cadera u
hombro, osteopenia y osteoporosis.
20
Stem Cell Transplants
Graft Failure/Rejection
• Graft failure
– Primary – prolonged pancytopenia with bone
marrow aplasia
– Secondary – initial engraftment then subsequent
decline of peripheral blood counts and loss of
donor graft
• Graft rejection
– Recipient cells reject against graft (donor) cells
Another complication of stem cell transplant is graft
failure or graft rejection. There are two types of graft
failure. The first is primary graft failure. This occurs
when the patient is given high-dose chemotherapy. The
stem cells are infused, but the patient’s counts do not
recover and hence the patient remains pancytopenic for
several months --- for several weeks (excuse me). When
assessing the bone marrow examination, the bone marrow
biopsy itself would be aplastic. The second form of graft
failure is secondary graft failure. This occurs when the
patient does have initial engraftment, which means their
counts do recover after the stem cell infusion. However,
over the subsequent weeks, the blood counts slowly
decline. When assessing the patient’s bone marrow or
peripheral blood, you notice gradual decline in the
amount of donor cells in the patient’s blood. This is
called secondary graft failure. In contrast to graft failure,
there is also graft rejection in which the patient is given
high-dose chemotherapy, stem cells are infused, the
patient’s counts recover, but when assessing the bone
marrow or peripheral blood, the recovered counts are the
patient’s and not the donor’s. And hence the patient has
rejected the graft and there are no graft cells in the
donor’s specimen --- (I am sorry) there are no graft cells
in the patient’s bone marrow or peripheral blood.
Otra complicación del trasplante de células madre es el
fallo o rechazo del injerto. Hay dos tipos de fallo.
El primero es el fallo primario, que ocurre cuando el
paciente recibe altas dosis de quimioterapia. Las células
madre son infundidas, pero los recuentos del paciente no
se recuperan y este permanece pancitopénico por varias
semanas. Al examinar la médula ósea, la biopsia muestra
aplasia. El segundo tipo es el fallo secundario del injerto.
Ocurre cuando inicialmente el injerto se adapta al
paciente, cuyos recuentos se recuperan después de la
infusión de células madre; sin embargo, en las semanas
siguientes, el recuento sanguíneo decae lentamente.
Al evaluar la médula ósea o la sangre periférica del
paciente, se observa una disminución gradual de las
células del donante en la sangre, que es el fallo
secundario. En contraste con los fallos del injerto,
también existe el rechazo: el paciente recibe altas dosis
de quimioterapia, se le infunden las células madre y sus
recuentos se recuperan, pero al evaluar la médula ósea o
la sangre periférica, los recuentos recuperados son los del
paciente y no los del donante. Por lo tanto, el paciente ha
rechazado el injerto y no hay células del injerto en su
médula ósea ni en la sangre periférica.
21
Stem Cell Transplants
Relapsed Disease
• Treatment
– Supportive care
– Reduction and discontinuation of
immunosuppression
– Chemotherapy
– Donor lymphocyte infusion
Stem Cell Transplants
Donor Lymphocyte Infusion (DLI)
• T cell lymphocyte infusion given after allogeneic
transplant with or without chemotherapy
• No immunosuppression given prior to infusion
• Can induce strong graft versus tumor effect
• Can increase or produce graft versus host disease
• Indicated for
– Relapsed disease
– Progressive disease
– Residual disease
• Contraindicated
– Active graft versus host disease
The final and almost worst complication is unfortunately
relapsed disease. In this setting, there are still potential
treatments for the patient. The patient can either choose
to pursue supportive care and not receive any further
treatment depending on how debilitated they are from
their primary transplant. Another treatment is to reduce
or discontinue the immunosuppression. So in the setting
of relapse you can always taper or decrease the
immunosuppression, i.e., the tacrolimus, and try to incite
some graft versus host disease. If the patient is
physically capable, you also can give chemotherapy by
itself and see what kind of response you get in the
patient’s disease.
La complicación final y casi la más grave es,
desafortunadamente, la recurrencia de la enfermedad.
En este contexto, aún existen tratamientos potenciales
para el paciente, quien puede optar por continuar el
cuidado de apoyo o no recibir ningún tratamiento
adicional, según el grado de debilidad después del
trasplante primario. Otra alternativa es reducir o
interrumpir la inmunosupresión. Si hay recurrencia,
siempre se la puede disminuir gradualmente (es decir, el
tacrolimus) y tratar de estimular la enfermedad de injerto
contra huésped. Si el paciente es físicamente capaz, se le
puede administrar solamente quimioterapia y ver qué tipo
de respuesta se obtiene.
The fourth and final treatment is called a donor
lymphocyte infusion. A donor lymphocyte infusion or
DLI is when you give T-cell lymphocytes to the
recipients.
This is either given with or without
chemotherapy. The T-lymphocytes are collected from
the donor without any growth factors or any other
stimulation. The T-cells are infused into the recipient
without any immunosuppression or no tacrolimus. You
hope to incite a strong graft versus tumor effect, but you
also can increase or produce graft versus host disease.
The reason being, is again, you are giving T-lymphocytes
without any immunosuppression. So the risk of graft
versus host disease increases. This type of treatment is
indicated in the relapsed disease setting, in [a]
progressive disease setting, and in patients with residual
disease after transplant.
A DLI is absolutely
contraindicated if the patient has active graft versus host
disease. By giving a DLI to a patient with active graft
versus host disease, you can incite fatal graft versus host
disease.
El cuarto y último tratamiento es la infusión de linfocitos
de donante. También se denomina DLI y consiste en
administrar linfocitos de células T al receptor. Este
procedimiento puede ser concomitante con la
quimioterapia. Los linfocitos T se recolectan del donante
sin usar factores de crecimiento u otros estímulos. Las
células T se infunden al receptor sin utilizar
inmunosupresión (como tacrolimus) para incentivar el
efecto del injerto contra el tumor, aunque esto puede
exacerbar o inducir la enfermedad de injerto contra
huésped, pues se administran linfocitos T sin
inmunosupresión. Esto aumenta el riesgo de desarrollar la
enfermedad. Este tratamiento está indicado en caso de
recurrencia o progresión, y en pacientes con enfermedad
residual postrasplante. La DLI está absolutamente
contraindicada si el paciente tiene enfermedad de injerto
contra huésped activa. Al infundir leucocitos de donante
a un paciente con enfermedad activa, esta puede
incentivarse y tornarse fatal.
22
Stem Cell Transplants
Late Complications
• Secondary malignancies
• Cirrhosis (multi-factorial, transfusions, toxicity of
prior chemotherapy, alcohol, hepatitis, GVHD)
• Late infections (CMV, fungus, encapsulated
bacteria)
In the late phase of transplant, there can be other
complications outside of infections. This can include
secondary malignancies, i.e., head and neck
malignancies. You also can develop cirrhosis or other
organ damage. And this can be multifactorial either from
prior chemotherapy, transfusion, hepatitis from drugs,
and also graft versus host disease. Again, late infections
are critical, CMV infection, fungal infection,
encapsulated bacteria, and also Epstein Barr related
infections.
En la fase tardía del trasplante puede haber otras
complicaciones además de infecciones, como tumores
malignos secundarios de cabeza y cuello. El paciente
también puede desarrollar cirrosis o daños en otros
órganos. Esto puede ser multifactorial, ya sea por
quimioterapia previa, transfusión, hepatitis por drogas y
también enfermedad de injerto contra huésped. Son
críticas las infecciones tardías por citomegalovirus,
micosis, bacterias encapsuladas y el virus de Epstein
Barr.
In the post-transplant setting, you also want to make sure
you re-vaccinate patients. Once patients are given their
high-dose chemotherapy, they lose all antibodies of prior
vaccinations and, hence, once they have no active
infections, and are off immunosuppression, there is a revaccination schedule.
This includes pneumococcal
vaccination, influenza, tetanus, [and] hepatitis B. In the
autologous setting, these vaccinations are given at one
year after transplant. In the allogeneic setting, these
vaccinations are given at least six months after
discontinuation of the immunosuppression. Again, the
patient can have no active infections and no active graft
versus host disease. In addition, in order to assess how
successful the transplant has been, you assess the
chimerisms. Chimerisms are quantitative analysis of
donor cells that can be assessed either via peripheral
blood or bone marrow. Staging is done every three
months post-transplant in the first year, and then every
six months thereafter, on year two and three, and then
annually. Bone densities and pulmonary function testing
is also assessed at six months and then clinically as
En la etapa de cuidado postrasplante debemos revacunar
a los pacientes. Una vez que reciben altas dosis de
quimioterapia, pierden todos los anticuerpos de las
vacunas anteriores. Por lo tanto, cuando no tienen
infecciones activas y ya no están inmunosuprimidos,
aplicamos un programa de revacunación
antineumocócica, antigripal, antitetánica y contra la
hepatitis B. En el trasplante autólogo, estas vacunas se
aplican un año después del trasplante. En el trasplante
alogénico, al menos seis meses después de interrumpir la
inmunosupresión. En estos casos, el paciente no debe
tener ninguna infección activa y tampoco enfermedad de
injerto contra huésped activa. Para valorar el éxito del
trasplante, también se evalúa el quimerismo, que es un
análisis cuantitativo de las células del donante a partir de
la sangre periférica o de la médula ósea. La estadificación
se realiza cada tres meses en la etapa postrasplante
durante el primer año, cada seis meses en el segundo y
tercer año, y luego anualmente. A los seis meses también
se evalúan las densidades óseas y las pruebas de función
pulmonar, y luego según el criterio clínico.
• Post transplant EBV related lymphoproliferative
disease (PTLD)
Stem Cell Transplants
Post Transplant Care
• Vaccinations
–
–
–
–
–
Pneumococcal, influenza, tetanus, hepatitis B
Given 1 year after autologous
Given 6 months after cessation of immunosuppression
No active infections
No GVHD
• Assessment of chimerisms
– Quantitative analysis of donor cells
• Staging every 3 months for 1 year then 6 months for 2-3
years then annually
• Bone density and pulmonary function testing at 6 months
then as clinically indicated
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Stem Cell Transplants
Stem Cell Transplants
Conclusions
• Stem cell transplant is an option for treatment of
various hematologic malignancies
• Stem cells can be collected from donors, umbilical
cord blood or from the recipient
• Ablative or reduced intensity chemotherapy is
administered prior to stem cell transplant
• In addition to potential advantages of graft versus
tumor effect, various serious complications may
occur including graft versus host disease, organ
damage and graft rejection
indicated.
This is a diagram of the allogeneic transplantation in
detail. The patient is given an ablative hematopoietic
regimen. The first figure you will see denoted by A is the
patient’s blood cells. The cells denoted by A with a
subscript 1 are the leukemia cells. The patient again as
stated above is given a preparative regimen. This B is
denoted by the donor cells that are given to the patient.
When assessing the patient, you note ---there is noted to
be some cells denoted by B in the recipient. However,
the patient is not full donor yet and there sometimes, a
donor lymphocyte infusion is required, in addition to
immunosuppression withdrawal, in order to incite
complete donor chimera as evidenced by the last figure.
Este es un diagrama detallado del trasplante alogénico.
El paciente recibe un régimen hematopoyético ablativo.
En la primera figura, la letra A indica las células
hemáticas del paciente. Las que tienen el subíndice 1 son
las células de la leucemia. El paciente recibe un régimen
de preparación. La letra B indica las células de donante
infundidas al paciente. Al evaluar al paciente, pueden
observarse algunas células indicadas como B en el
receptor; sin embargo, el paciente no es todavía donante y
a veces se requiere una infusión de linfocitos del donante,
además de la interrupción de la inmunosupresión, a fin de
estimular una quimera completa del donante, tal como lo
indica la última figura.
In conclusion, stem cell transplant is an option for
treatment for various hematologic diseases. Stem cells
can be collected from donors, umbilical cord blood, or
from the recipient, depending on which type of transplant
the patient will receive. Ablative or reduced intensity
chemotherapy is given prior to the stem cell transplant.
In addition, there are potential advantages of graft versus
tumor effect in the allogeneic setting. However, there are
various serious complications that occur in the posttransplant setting to include graft versus host disease,
organ damage, and graft failure. With all this being said,
allogeneic transplants have the best chance of improving
the patient’s overall survival, particularly in patients with
relapsed disease who most likely will no longer respond
to standard chemotherapy. Thank you very much for
your time and attention. Please let us know if this
presentation has been useful to you.
El trasplante de células madre es una opción para el
tratamiento de diversas enfermedades hematológicas. Las
células madre pueden obtenerse de donantes, de sangre
de cordón umbilical o del receptor, en función del tipo de
trasplante a realizar. Antes del trasplante de células
madre, se administra quimioterapia ablativa o de
intensidad reducida. Además, en los trasplantes
alogénicos, existen ventajas potenciales del efecto del
injerto contra el tumor. Hay varias complicaciones graves
en la etapa postrasplante, como la enfermedad de injerto
contra huésped, daños orgánicos y el fallo del injerto. Por
último, los trasplantes alogénicos son proclives a mejorar
la supervivencia general, sobre todo en pacientes con
recurrencia que probablemente ya no respondan a la
quimioterapia estándar. Le agradezco su tiempo y
atención, y espero que nos haga saber si esta presentación
le ha resultado útil.
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