Dr. Peter Marks, Understanding Acute
Leukemias
January 17, 2010
Welcome to Yale Cancer Center Answers with Dr. Ed Chu and Dr. Francine Foss. I am Bruce Barber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Dr. Foss is a Professor of Medical Oncology and Dermatology specializing in the treatment of lymphomas. If you would like to join the conversation, you can contact the doctors directly. The address is canceranswers@yale.edu and the phone number is 1888-234-4YCC. This evening Ed and Francine welcome Dr. Peter Marks. Dr. Marks is an Associate Professor of Hematology at Yale School of Medicine, Chief Clinical Officer at Smilow Cancer Hospital, and an expert in the research and treatment of leukemia.
Foss
We are here today to talk a little bit about leukemia. I know there
are lots of different types of leukemia, so can you just go through
briefly what those different types are and how patients are
diagnosed?
Marks
There are two broad categories of leukemia; acute leukemias and
chronic leukemias. Acute leukemias tend to have relatively
rapid presentations. Usually patients are diagnosed because
they present with something that becomes notable or noticeable to
them, such as they develop bruising or bleeding, or they might
develop recurrent infections or they feel fatigue. These are
things that people generally cannot ignore and end up coming to the
hospital to see a physician or going to their primary care doctor
and seeing them. On the other hand, there are the chronic
leukemias which tend to develop over the course of long periods of
time. They tend to come to medical attention either
incidentally or because somebody notices a lump or bump for
instance, or they might notice abdominal fullness after they are
eating, and that is a different type of
presentation.
Foss
Peter, given that both acute and chronic leukemias could be the
subject of a whole show, today I would like to focus only on the
acute leukemias. Could you backtrack just for one minute for
our audience and explain what leukemia is? Everybody knows
leukemia is a disease of the blood, but I am not sure that people
understand exactly what it is.
Marks
To step back, I think it is important to understand that leukemia
is basically another way of saying a cancer that affects the blood
forming cells in the bone marrow. Just like there could be a
breast cancer, which is of tissue of the breast, or a colon cancer
of tissue of the colon, the bone marrow which produces blood cells
is a tissue just like any other, and leukemia is a cancer that
occurs in one of the cells in that tissue. It occurs from a
cell that goes awry and then continues to divide when it should
not. And normally that process of blood cell division is very
well controlled, but when one particular cell loses its normal
control mechanism, it keeps growing and growing and it essentially
crowds out the normal tissue that would be there, the normal blood
forming cells, and that creates many of the problems that we see in
leukemia.
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Foss
So fundamentally, all leukemias arise within the bone marrow?
Marks
Pretty much so, there are rare presentations of leukemia where we
see the major focus of leukemia outside of the bone marrow, but in
general, they come up in the bone marrow.
Foss
And you talked a little bit about patients developing fullness in
their abdomen and a little bit about the symptoms of
leukemias. Can you tell us what other organs in the body are
involved with leukemia?
Marks
In general, most patients with leukemia, when they come to medical
attention, may notice that they have bruising on their skin or
bleeding in their mouth. And sometimes patients will have
frequent upper respiratory tract infections. Those are the types of
things that we see in acute leukemias where people have
symptoms. We tend to see fewer presentations of people
complaining of large lymph nodes or swollen glands, and fewer
presentations of people who are complaining of feeling abdominal
fullness, which would be more common in the chronic leukemias.
Foss
We use the word acute to mean something that has happened very
quickly. Can you give us an idea of how quickly acute
leukemia can come on?
Marks
There is a spectrum of how fast acute leukemia can come on.
We know from some people who have had normal blood counts a few
weeks prior to coming to medical attention with leukemia, that at
least in terms of the abnormalities in blood counts and symptoms it
can come on in only a matter of 2 or 3 weeks. That does not
mean that the first leukemic cell became apparent in the body then,
but it means it's the first time anything measurable that we can
see in the laboratory becomes noticeable. On the other hand,
some people can actually take months to years to develop acute
leukemia in certain settings, and there it is not truly acute, it
is sub-acute, but that is a different story.
Foss
Peter, can you talk a little bit about the risk factors for
leukemia?
Marks
In general, and I think this is a key message, for the majority of
leukemias' we still don't know what the causes are. There are
certain things that do place one at increased risk for
leukemia. Exposure to radiation is clearly a risk factor.
We know that from people who have had exposure either to
nuclear accidents or other scenarios. We also know that
exposure to certain chemicals can cause acute leukemia, can be
associated with it; also people who have had exposure to benzene or
other organic compounds. And then increasingly, we understand
that a certain population of people, those who receive certain
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chemotherapies for cancer, are at risk for therapy-related leukemias that occur because some of the treatments that we give can alter the blood-forming cells and lead to leukemia.
Foss
When you talk about radiation, there has been a lot in the
newspapers recently about the medical use of radiation in terms of
CAT scans and chest x-rays. Is that sufficient radiation to
induce leukemia, and should the average person be worried about
that?
Marks
To the best of my knowledge the amount of radiation during those
diagnostic studies presented to individuals is not anything that
really is of concern. If there is a good reason why someone
is going to need a chest x-ray or CT scan, they should have it
because the increased risk is really not noticeable in the scheme
of things.
Foss
Thank you Peter. I think it is really important for our listeners
to be able to put all that into perspective. Just a little
bit more about the chemical exposure, a lot of people may or may
not be exposed to chemicals at their work place, or potentially to
chemicals in the home. To what degree do they really need to worry
about that?
Marks
Today we are very lucky in that with increasing awareness there are
various standards that have been placed on occupational exposures
and home exposures of chemicals that could potentially put one at
risk for leukemia; many compounds we simply don't come in contact
with the way we used to. Probably a good practice is to
minimize your exposure to anything, but I think the chemicals that
are really at the greatest risk have occupational exposures that
are monitored and you cannot even get a hold of them at home.
Foss
What about the genetics issue with leukemia? First of all, is
it inherited? If somebody in your family has leukemia, do you
need to worry about leukemia?
Marks
That is a somewhat complicated question to answer, but I will try
to answer it in a way that makes some sense of it. For a very
large majority of people with leukemia, there is no genetic
component that we are aware of, and that is probably 95 plus
percent. There are a small number of patients who have
leukemia where if you look back, they either have some family
history of an increased frequency of leukemia, or they have certain
genes that place them at increased risk of leukemia. But for
the very large majority of people who have leukemia, we have no
genetic basis that we can find, at least today, that is the cause
of their leukemia. Another question that sometimes gets asked
is, is leukemia transmissible from person to person in the
home? If you have a person who has leukemia, can those cancer
cells go from one person to another easily? And that is not
something that happens.
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Foss
What about the average age of patients with leukemia?
Marks
Leukemia can happen across the entire age spectrum. Acute
leukemias occur across the entire spectrum from children to very
old adults. And in fact, most adults with acute leukemia, the
most common acute leukemia which is acute myeloid leukemia, have a
median age of onset of about 68 years. So the majority of
people with acute myeloid leukemia will be over 65 years old.
Foss
Is there any difference whether you get leukemia when you are
younger or when you are older?
Marks
There is, our ability to cure people successfully with acute
leukemia really depends on the age of onset, and I will give you
two extremes of this. With acute lymphoid leukemia, which is
one type of leukemia that primarily effects children, we are now
successful in curing more than 90% to 95% of the children who come
down with this, when they are diagnosed in the age range of 4 to 8
years old. So we are very, very successful in that
leukemia. At the other extreme, when we have acute myeloid
leukemia, which is the common form in older individuals, if it is
diagnosed in someone in their 70s, we probably cure less than 10%
of those individuals. So it is a real big difference based on
the type of leukemia and the age of the individual.
Foss
So the approach for the individual patient then really depends on
the number of different factors like their age and the subtype of
leukemia that they have?
Marks
That is correct.
Foss
It is difficult when you think about the prognosis of leukemia, to
really pinpoint one specific prognosis for everybody.
Marks
That is absolutely correct. And increasingly we are finding
broad prognostic categories based on age, based on types of
leukemia, and also now, increasingly based on the molecular makeup
of the leukemias.
Foss
There has been a lot of research in leukemia recently, Peter,
looking at those molecular subtypes and sub dividing patients, as
you had mentioned, do you feel that that is changing our approach
to leukemia?
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Marks
Yeah, more so than any drug that has been developed. I think
the largest change over the past decade or two is not new drugs, it
is that we have a better understanding of who is likely to do well,
who we need to treat very aggressively, and who we can treat less
aggressively. That has come from an understanding of the genetic
composition of these various leukemias.
Foss
Can we take a step backward at this point and think about the
individual patient who is diagnosed with leukemia? First of
all, how do you make the diagnosis? What kind of work-up does
that patient have? And what are the expectations for their
treatment at the beginning?
Marks
The diagnosis is usually made after a patient has presented with
some symptom that ultimately leads to a patient having a complete
blood count. When that complete blood count is abnormal, one
of two things can occur, either the complete blood count is very
abnormal with a very high number of white blood cells, in which
case the diagnosis can actually be made from just the blood count
and work on the peripheral blood, that is blood taken from the arm
or a vein, and we can make the diagnosis there. Or, when we
have somebody who has low blood counts, or the blood counts are not
very elevated, we sometimes have to do a test called a bone marrow
examination where we take some of the bone marrow, a chip of bone,
or some of the liquid bone from either the pelvis or some other
location of the body in order to analyze it to make the
diagnosis.
Foss
Peter, I would like to talk a little bit more about the treatment
for leukemia when we come back after the break. You are
listening to Yale Cancer Center Answers and we are here discussing
treatment options for patients with the acute leukemia with Dr.
Peter Marks.
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Foss
Welcome back to Yale Cancer Center Answers. This is Dr.
Francine Foss and I am joined by my co-host Dr. Ed Chu, and Dr.
Peter Marks, an expert on leukemia from Yale Cancer Center.
Peter, we talked a lot about who gets leukemia and how it is
diagnosed, but can you tell us how we treat leukemia?
Marks
Treatment of leukemia depends on the type of leukemia that a
patient has, and since we are talking about acute leukemias today,
we would divide it up into the two major types of leukemias, acute
myeloid leukemia and acute lymphoid leukemia. For younger
individuals, people say less than 65 years of age, both of those
are generally treated with systemic chemotherapy and usually a
variety of different drugs that may be given over the course of a
number of months. Sometimes these individuals even need to
have a stem cell transplant. For other individuals, older
people, and we said previously that people with acute myeloid
leukemia tend to be older, sometimes we actually defer giving
chemotherapy, or we will give very gentle chemotherapy and will
mainly use supportive care measures, blood transfusion as needed,
and antibiotics in order to support people through their
illness.
Chu
The chemotherapy drugs that are used to treat acute myeloid
leukemia versus acute lymphoblastic leukemia, the two most common
acute leukemias, are they the same or different? Or perhaps they
kind of complement one another?
Marks
Some of the drugs overlap, but there is a different approach
because acute myeloid leukemia is a disease that generally responds
to one or two different drugs given over the course of several
months that hopefully eliminates the disease entirely. On the
other hand, acute lymphoid or acute lymphoblastic leukemias,
actually require many different drugs to be given over a very long
period of time on the order of years to eliminate it. There
is one specific type of acute lymphoid leukemia, one that has a
very specific genetic makeup. A quarter of people over the age of
60 will have a type of acute lymphoid leukemia in which there is a
particular genetic abnormality that is a rearrangement of a gene
called the BCR-ABL gene, which makes leukemia sensitive to an oral
drug called imatinib, and in that case, we cant treat those
individuals with that oral drug sometimes successfully for quite a
number of years without ever having to give chemotherapy.
Foss
There is also a type of acute leukemia, a myeloid leukemia, which
has a specific gene for which we have a specific therapy also.
Marks
That is right, and there is a particular type of leukemia that
constitutes about 10% of acute myeloid leukemia called acute
promyelocytic leukemia. That is a leukemia where we now
understand that the administration of a particular drug called
all-trans-retinoic acid dramatically improves our ability to cure
the disease. It also dramatically reduces the
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number of people who die from complications of that disease. One of the real challenges in treating that disease previously was that it is a type of leukemia that is associated with activation of the coagulation system, so the people who presented with that would have tremendous amounts of bleeding, and they would often die before we could treat them from bleeding into their brain, or they would die as we treated them with bleeding into the brain, or otherwise. Now, with this particular treatment all-trans-retinoic acid, we give that before we give any chemotherapy and it seems to get rid of this bleeding tendency such that we have put a large majority of those people into long-term remissions, and in fact, that is a type of leukemia where, with current treatment, about 80 % of people are cured of their disease.
Foss
And that is basically a retinoid which is a derivative of vitamin
A?
Marks
That's correct.
Foss
And another kind of leukemia, I guess, can be treated with arsenic,
which is a drug that we have all heard of and is a toxin, but
potentially also a therapeutic.
Marks
Right, it is actually that same leukemia, acute promyelocytic
leukemia, and we also know that in that particular leukemia, the
combination of all-trans-retinoic acid and arsenic trioxide can be
used together for people who cannot otherwise take chemotherapy,
and can lead to some very good complete responses and potentially
cure. There is a good example of a 'targeted therapy',
although some people might not consider arsenic their classic
example of a targeted therapy, it does seem to work in patients
with that particular leukemia to target the leukemia and eliminate
it.
Chu
It is interesting that arsenic trioxide, and I think also
all-trans-retinoic acids, were originally derived from Chinese
herbal medicines.
Foss
That is right.
Marks
That is correct. These are both developments that came over
to western medicine from China and the advances came through and
were adopted relatively quickly and it made a huge difference here
adopting those medicines.
Foss
Peter, can you talk about the role of bone marrow transplant in
leukemia?
Marks
Bone marrow transplant, some people get confused when we say bone
marrow transplant and hematopoietic stem cell transplant, but we
are going to use them interchangeably here, just
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has to do with the source of where these cells come from, but bone morrow transplant, or hematopoietic stem cell transplant, has an integral place in the treatment of acute leukemias in adults. We use them to treat patients who have any type of poor risk feature that would lead them to be less likely to be cured by conventional chemotherapy. And unfortunately, the majority of adults who have acute leukemia, particularly myeloid leukemia, often have risk factors that make them do less than well. We tend to use it as a way to make sure that leukemia stays away for good. Without stem cell transplant or bone marrow transplant, we probably cure overall, in adults, a quarter to a third of people with acute myeloid leukemia. That number is doubled by having a population of patients go on to bone marrow transplant. Our age limit for bone marrow transplant now continues to get older and older, so that we actually have people who get reduced intensity types of bone marrow transplants into their 70s.
Foss
The important thing when you think about a transplant is that this
is not actually a cure for the disease itself, this is a way to
keep a patient in remission.
Marks
That is one of the ways to think about it. If you look at the
number of people that are 5 years out of disease, which we quite
often think of as cure, it is a way to make that happen.
Chu
Peter, you have been involved in treating patients with acute
leukemias for quite sometime now. Looking at things in
retrospect, what would you say have been the most significant
advances over the past 5-10 years both in terms of, I guess,
standard treatment options as well as the supportive care approach
to these patients?
Marks
I think the largest advance, that I really appreciate, is that by
understanding the genetic composition, leukemia is now at a better
level than we ever have had before. And I think we are going
to make very rapidly make more advances in the coming years.
We understand who will benefit from our standard therapies, and who
requires intensive therapy, and that will allow us to give patients
the minimum amount of treatment they need to be long-term
survivors. That way, we will not have people getting
high-dose chemotherapy who don't need it, and people will go on to
get high-dose chemotherapy that really need it because of these
genetic factors that we are able to do. And that is one of
the goals at a place like Smilow Cancer Hospital, the goal here is
to increasingly be able to do personalized medicine so that we
understand the actual genetic makeup of the leukemia, and then,
address that with our therapy; that is one of the goals. Then
another piece of it is that our supportive care has made huge
advances over the past number of years. We are better in
terms of our antibiotics. We have oral antifungal agents
which we did not have a large number of previously that help
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us to keep people's infections at bay, or prevent them entirely, so supportive care is a large aspect of what we do.
Foss
There are also some monoclonal antibody therapies for
leukemia. We talked about those in the context of other solid
tumors and lymphoma. Can you talk a little bit about
those?
Marks
The monoclonal antibody that probably is most relevant to acute
myeloid leukemia is an antibody that is linked up to a toxin, so
that the antibody kind of serves as a Trojan horse to get this
killer molecule into the leukemia cells and that particular
antibody, one of them is called gemtuzumab, is very useful,
particularly in older patients, where it can be given in a manner
to patients who could not tolerate other therapies safely. We
are also increasingly using it in combination with other drugs as a
way of salvaging patients, that is getting patients who have
relapsed with their leukemia back into their remission.
Foss
Is there any role for radiation in the treatment of acute
leukemia?
Marks
Occasionally there will be a role for radiation therapy.
Sometimes people will have a mass of leukemic cells and radiation
can be used to melt that away relatively quickly. In
addition, sometimes people have leukemia that can just affect the
skin, or mainly affect the skin, and there a special form of
radiation therapy to the skin can be used.
Chu
Peter, you have been pretty actively involved in the past in terms
of trying to develop new drugs for leukemias. Are there any
interesting clinical trials that are available for patients?
Marks
We are increasingly developing a portfolio of trials that will
involve various drugs. Right now we are kind of in between a
number of trials but we are bringing more and more ones online and
we are looking in particular to use drugs that are either standard
drugs in novel combinations, or newer drugs that have less toxicity
than some of their older counterparts. Aside from what we are
trying to do here at Yale, patients can always go to the National
Institutes of Health and the National Cancer Institute websites to
look for clinical trials in their area. There are also
support groups that are aware of clinical trials such as the
Leukemia and Lymphoma Society.
Foss
You have done a lot of work in the hospital with older people with
leukemia and you have developed some interesting combinations using
new drugs such as histone deacetylase inhibitors and DNA
methylation modulating agents. Can you talk a little bit
about the role of those kinds of new therapies in older
patients?
Marks
The treatment of leukemia in older patients takes into
consideration many different factors.
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It has to do not just with the patient's condition, but also what the patient's goals of therapy are. There are people who are 75 years old who have very different goals in life. Some people's goals may just be they want to have the next year or two and be able to see a major event happen, others have the attitude of they want to have 10 more years to go out and do many different things in their retirement. And so one has to take into consideration what somebody's goals are and with that in mind, one can take either a very minimalist approach, or one can use some of the regimens that we have tried to develop here using combinations of drugs that can be administered with modest toxicity, in other words regimens that can be given as an outpatient and tend not to require hospital admission. We combine drugs, for one example, a drug called decitabine which can be given as an outpatient can be combined with the antibody we talked about before, gemtuzumab, and that allows us to administer therapy in the outpatient setting that is reasonably well tolerated.
Chu
Do older patients intrinsically have a different level of response
to the drugs and the antibodies that you have talked about?
Marks
Well, we understand now that if you take the older population
overall as a group, they clearly have a lower response rate to the
drugs that we give. Going back to this discussion we had of
molecular and personalized markers, it is clear that there are
certain markers that seem to indicate that even an older individual
will respond relatively well to a given therapy. As we
understand this more and more, we may be able to pick out certain
older individuals who we will treat with conventional therapies
because we think that we will cure them and they will do very well
over the long run, and then, the remainder of the population who
we'll think about for other more novel treatments.
Chu
Peter, as always, it has been great having you on the show and we
look forward to having you back on a future show to give us an
update on the treatment and approach to patients with acute
leukemias.
Marks
Thank you very much.
Chu
You are listening to Yale Cancer Center Answer and we would like
to thank our guest Dr. Peter Marks for joining us this
evening. Until next time, I am Ed Chu from Yale Cancer Center
wishing you a safe and healthy week.
If you have any questions or would like to share your comments, you can go to yalecancercenter.org where you can also subscribe to our podcast and find written transcripts of past programs. I am Bruce Barber and you are listening to the WNPR health forum from Connecticut Public Radio.