Practice English Speaking&Listening with: Brian Druker (OHSU) Part 1: Imatinib (Gleevec): A Targeted Cancer Therapy

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Hello, my name is Brian Druker from the Oregon Health and Science University Cancer Institute.

The topic of my talk today is Imatinib, or Gleevec, as a paradigm of targeted cancer therapies.

What I'd like to do in the first part of my talk is discuss chronic myeloid leukemia

and the development of imatinib as a specific targeted therapy for this disease.

I'll start with a clinical description of CML, then discuss the molecular pathogenesis of CML,

followed by how that understanding led to the development of imatinib,

both through its pre-clinical and clinical phases.

Now, for those of you who, that know chronic myeloid leukemia, you know that it in fact is relatively rare disease.

But I really need to have you think of this as a paradigm.

So, in order for you to think of this as a paradigm, I'd like to show you a movie clip from a movie titled "Dr. Ehrlich's Magic Bullet."

If the cause has been discovered, there's hope for a cure.

And when you think about what I'm talking about today, I want you to really think about your own favorite disease,

and if you understand the cause, then there's hope for specific, targeted therapies that can be quite effective.

Now, I'll use CML as our paradigm for today, but this really is a generalizable phenomena, as we'll discuss.

So, when we think about chronic myeloid leukemia, we first have to understand the molecular pathogenesis,

but before that, we also need to describe the clinical entity.

So, the clinical entity of CML was first described in 1845.

About 140 years later, the molecular pathogenesis was understood

and then in 2001, a specific therapy was developed.

Now, I actually view this slide as the heart and soul of translational research.

You describe a clinical entity, understand its molecular pathogenesis and use that knowledge to develop a specific therapy.

But one of the lessons we learned in the clinical trials of imatinib is that translational research doesn't end when you go into the clinic.

In fact, we need to understand how our therapies work,

why they work, who they work best for, so in other words, is, we get into the clinic,

we actually need to go back to the lab to understand some of those issues.

And, for example, why do some patients relapse, as we'll discuss.

As we begin to understand that, we can then go back into the clinic with even better therapies.

And we then begin a translational research cycle.

And I'll demonstrate how that worked in our clinical trials of imatinib as well.

So, it's absolutely clear that we can certainly do better than 150 years of discovery,

but I'd also just like to take you through this briefly.

And we'll start with a clinical description of chronic myeloid leukemia in 1845

by two pathologists, Dr. Bennett and Dr. Virchow.

Now, these two pathologists, without staining methods for blood,

described the clinical phenomena of chronic myeloid leukemia based on autopsy findings.

Now, in 1845, these two pathologists published these papers within 6 weeks of one another.

Now, as you might imagine, there ensued a vigorous debate about who was really first,

ultimately Virchow capitulated that Bennett has described CML six weeks prior to him.

Fast-forwarding, we now know that chronic myeloid leukemia makes up about 15 to 20 percent of all leukemias

and it is one of the four common types of leukemia.

There are about 1 to 2 cases per hundred thousand per year,

and the incidence of CML is relatively even world-wide.

In the United States, its incidence translates into about 5,000 new cases per year.

Although the disease can affect any age group, the average age of onset is in patients 50 to 60 years of age.

The disease itself has three recognizable phases.

The so-called chronic, or stable, phase, in which 95 percent of patients will present, hence the name, chronic myeloid leukemia.

However, the disease does progress over time through an accelerated phase

to a blast crisis, and it's these two phases that are collectively referred to as advanced phase disease.

In the chronic phase of the disease, it's characterized by a massive expansion of white blood cells.

So, for example, a white blood cell in a patient at diagnosis

will be anywhere between fifty to five hundred thousand.

For reference, a normal white blood count is between five to ten thousand,

so you can see the white blood count at diagnosis is between five to fifty times the upper limit of normal.

But the white cells mature completely normally and function normally.

They're just too many of them.

So, we don't see infections or susceptibility to infections as a manifestation of this type of leukemia.

If you look at a typical blood smear of a patient with leukemia,

you see a full spectrum of white blood cell lineages.

So, here you see some immature white blood cells,

here you can see we have basophils,

but you also see that there are lots and lots of mature and maturing white blood cells.

In fact, this almost looks like a bone marrow aspirate,

because of the maturation of white blood cells through the entire lineage.

So, in the stable phase of the disease, which historically has lasted 4 to 6 years,

we currently actually don't know how long the stable phase lasts with the current improved therapies,

like imatinib, which I'll cover very soon.

However, the problem with this disease, or historically the problem with this disease,

is that a malignant clone loses its capacity for terminal differentiation

and the disease progresses to a highly treatment refractory acute leukemia.

And by the time you get to this highly refractory blast crisis stage,

survival is measured in mere months.

So, typically no more than 3 to 6 months when a patient evolves into the blast crisis.

Now, if we're going to do anything or make an impact on this disease,

we need to understand the causes of this leukemia.

So, here we go back to, again, two pathologists: Peter Nowell and David Hungerford.

In 1960, they published this landmark paper in Science

that showed an abnormal chromosome in the blood cells and bone marrow of patients with chronic myeloid leukemia.

Now, this paper is the entire three paragraph Science paper.

Now, that tells you immediately that quality doesn't equate with, quantity doesn't equate with quality.

Now, as you know when you write a paper, in the last paragraph, you can sort of wax philosophical

about the broad implications of what your findings mean.

And if you look here at their very last paragraph, what they said was that the finding suggests a causal relationship

between the chromosome abnormality observed and chronic myeloid, or chronic granulocytic, leukemia.

Now, in 1960, nobody believed them.

Everyone was skeptical about this and they thought it was just an associated abnormality

that had nothing to do with the pathogenesis.

As it turns out, Nowell and Hungerford were well ahead of their time in recognizing how important their finding truly was.

Then in 1973, Janet Rowley, pictured here,

showed that this short chromosome 22

actually came about because a reciprocal translocation between the long arms of chromosome 9 and chromosome 22.

And as a result of that, you end up with a short chromosome 22,

as well as a slightly longer chromosome 9.

Now, by the 1980's, it became recognized that as a result of this chromosome translocation,

all of the Abelson tyrosine kinase, which is located on chromosome 9,

had been translocated into this break point cluster region,

or BCR, on chromosome 22. The chromosome breaks on chromosome 22

occurred between what's historically called the second and the third exon of the break point cluster region.

Now, as a result of that chromosome translocation, we end up with this fusion protein,

or RNA, called p210 BCR-ABL. And it includes either the second or third exons of BCR

fused in-frame to virtually all of the Abelson tyrosine kinase.

So, if we think now historically about chronic myeloid leukemia,

the reality is there's lots and lots of research that went into these discoveries.

So, if we think historically, actually, the discovery of a tyrosine kinase, like BCR-ABL,

actually had its roots from Rous sarcoma virus, which ultimately led to the discovery of the SRC oncogene

and somewhat later, the ABL oncogene.

And once the ABL oncogene was discovered,

it immediately was recognized that the BCR-ABL oncogene was a related event with oncogenic potential.

But in addition, as it also related, there's another thread that came from chromosome banding

that allowed gene mapping that allowed the assignment of BCR and ABL to the chromosomes 9 and 22.

But lastly, there was the entire field of protein phosphorylation.

So, beginning in the late 1930's, with the identification of protein kinases,

then in 1979 Tony Hunter discovered tyrosine kinases

and it was immediately recognized that SRC was the founding member of the tyrosine kinase family.

ABL was also identified as a tyrosine kinase and once BCR-ABL was identified,

it could be shown it was also a tyrosine kinase.

So, if we think about all of these events over the past 100 years,

there's a thread from tumor virology, a thread from protein kinases and phosphorylation,

and a thread from chromosome mapping and chromosome banding.

So, the points of this slide are several. First of all, we have a convergence of several different fields.

You can end up with remarkable breakthroughs that lead to specific therapies like imatinib.

But in addition, it tells you that there are literally thousands of researchers that are participating in this discovery process

over the past 100 years. Many, many investigators have made small incremental advances

that have led to a very big picture that allows major breakthroughs.

And so, for those of you that are working in laboratories or thinking about research careers,

the reality is there are many, many ways to make contributions.

I have the advantage of being able to look back over a hundred years now,

seeing how all of this has come together that's allowed an advance like imatinib.

So, now we're ready to talk about the development of imatinib

because we understand the molecular pathogenesis. So, here we have an ideal therapeutic target:

BCR-ABL. It comes from a fusion gene and protein that was generated by this 9 :22 chromosome translocation.

It's actually detected in all patients with chronic myeloid leukemia and we know from animal studies

that if you put BCR-ABL into mice, they develop leukemia.

This is an oncogenic event that causes leukemia.

We also know that the protein BCR-ABL functions as a constitutively activated intracellular tyrosine kinase.

And this kinase activity is absolutely required for its function.

So, we think about this schematically, and for those of you that don't think about tyrosine kinases every day

like I have for the past 20 years, this is a schematic of a tyrosine kinase.

So, what does a kinase do? In the case of any kinase, they bind ATP

and in the case of tyrosine kinases, they transfer phosphate from ATP onto specific tyrosine residues of substrate proteins.

And it's these substrate proteins that induce all the phenotypic abnormalities we see in CML.

The high white count, the excessive proliferation, presumably also protection from apoptosis,

and possibly even the genetic instability that leads to blast crisis.

So, if you could imagine, if you could block binding of ATP to this specific tyrosine kinase,

you'd have an ideal therapeutic agent for this disease.

And that's exactly what we did in the STI, or imatinib program.

So, beginning in the late 1980's, in collaboration with scientists at what was then Ciba-Geigy

and ultimately became Novartis pharmaceuticals, they were interested in developing kinase inhibitors.

Now, in fact, they weren't interested in chronic myeloid leukemia because of the relatively small market,

but they had other major kinases, like the epidermal growth factor receptor, or the platelet derived growth factor receptor,

and they had large libraries that they could run through robotic screens of their favorite tyrosine kinase.

So, for example, looking at the PDGF receptor, EGF receptor, they could run large library screens,

and end up with a lead inhibitor.

Now, this lead inhibitor was relatively impotent, not terribly potent,

and really not very specific.

But what they could then do with this lead compound is they could synthesize related compounds,

go back and screen against their favorite tyrosine kinase,

find some inhibitors that were better, some inhibitors that were worse.

But then by looking at what features allowed their inhibitors to be better or worse,

they could then go back and synthesize related compounds again.

And then by repeating this cycle several times,

they actually ended up with very potent and selective inhibitors of their favorite tyrosine kinases.

Now, in the original project, the kinase that they were looking at was a platelet derived growth factor receptor,

but as they optimized against the PDGF receptor, they carried along ABL inhibitory activity.

Then, in 1993, Nick Lydon from Ciba-Geigy sent me the best of their dual PDGF receptor ABL inhibitors

and our laboratory showed that the best compound they had at specifically killing CML cells

was this drug we now know as imatinib, or in the old days I knew it affectionately as CGP 57148.

It then picked up a name of STI 571 and interestingly enough,

it's Gleevec with two e's in the United States and Glivec with an i in the rest of the world.

And that's actually a pretty funny story about how that happened.

When Gleevec went to the Food and Drug Administration in the United States,

as well as all the similar regulatory agencies around the world, it went as Glivec with an i.

Now, as the story goes, the FDA wrote back to Novartis that they had a problem:

that Gleevec was going to get mispronounced as "gly-vec"

and that meant that it was going to get confused with a number of diabetes drugs that were on the market.

Like glyburide and others. So, Novartis wrote back to the FDA, how about if we spell it phonetically in the United States

with two e's, Gleevec. With two e's, the FDA accepted that

and despite that, Gleevec still made it through in less than six weeks,

and still holds the record for the fastest drug that made it through the FDA.

But, nonetheless, it's still Gleevec with two e's in the United States,

Glivec with an i throughout the rest of the world.

Now, we actually knew when we got this compound that we had a specific inhibitor of the BCR-ABL tyrosine kinase,

as well as all the other Abelson tyrosine kinases, as well as the PDGF receptor.

But my laboratory also showed that it inhibited the KIT tyrosine kinase

and when we talk about the gastrointestinal stromal tumors, you'll see exactly why that was important.

We also tested as many different kinases that we could get our hands on,

and showed that we had a very, very selective inhibitor, inhibiting only those three, but no others.

For example, EGF receptor, insulin receptor family, as well as a variety of other transmembrane receptors,

like FLT-3 and the CSF-1 receptor, and none of the intracellular tyrosine kinases, like the JAK family or the SRC family.

So, for those days and even now, even more so, this was a very selective inhibitor of tyrosine kinases.

Just to show you some of our pre-clinical data, this is an anti-phosphotyrosine immunoblot

that shows increasing doses of imatinib. So, we start with very low doses

and then move on to very high doses.

And you can see at the low doses, there's very little inhibition of tyrosine phosphorylation,

but you can see a very nice dose-dependent inhibition as we increase the dose of imatinib.

And this band up here is the BCR-ABL tyrosine kinase itself.

Now, just to show that we're not inhibiting the protein,

this is an ABL immunoblot that shows you that there's no inhibition of the protein expression.

So, we're seeing a specific effect on the kinase activity.

When we now go to cells, these are actually cells, either parental cells or cells that are engineered to express BCR-ABL,

and you can see that the parental cells and BCR-ABL cells, in the absence of imatinib, grow very, very nicely.

But if we now we incubate the BCR-ABL expressing cells in the presence of as little of 1 micromolar imatinib,

these cells are dead within two to three days.

And it's a specific effect on cells that express BCR-ABL.

If we now go to animal models, this is just a dose-finding study,

where we start with either placebo or increasing doses of imatinib injected as up to 50 milligrams per kilogram, once per day.

These are established tumors that we start with over here,

and we're just looking at whether we inhibit the growth of the tumors or not.

And you can see a very nice dose-dependent decrease in the growth of these tumors.

This is specific to BRC-ABL expressing tumors, we don't see this activity against other types of tumors,

for example v-SRC expressing tumors.

So, to summarize our pre-clinical data, imatinib is a potent selective inhibitor of the ABL, PDGF and KIT tyrosine kinases.

We can show that imatinib selectively kills BCR-ABL expressing cells,

both in vitro, as well in vivo in our animal models.

Now, as it turns out, the chemists at Novartis were able to make this into a highly bio-available oral formulation.

What that meant was that when we went to clinical trials, we actually had pills that we could use,

we didn't have to hook patients up to IV's.

Now, I wish I could tell you that everything went very smoothly,

and relatively quickly, but the reality is there were lots of hurdles to getting this drug into the clinic.

And there were many, many reasons that came up why imatinib should never be developed.

The first was lots of skeptics thought that kinase inhibitors would never work.

A kinase inhibitor had never been used in man, or humans, before,

so the view was that if we shut down some of these kinases, they probably aren't that critical of a target

and they probably won't work.

So, there was still a lot of skepticism about whether BCR-ABL was the right target.

The next concern was that these kinase inhibitors will be terribly toxic.

Although we had done a lot of profiling, a lot of preclinical toxicology,

there were some hints that we might see some toxicity in our human studies,

but because this type of agent had never been given to people,

there was a lot of concern about whether it might see a lot of toxicity.

But the biggest concern from a drug company was that these kinase inhibitors, at least for CML,

would never make enough money to justify their development.

So, if we think a drug development, it can cost as much as 500 million to 1 billion dollars

to make back, to develop a drug. And if you think about chronic myeloid leukemia, I said 5,000 cases per year in the United states,

that might never be enough to justify its development.

Now, as it turns out, all three of these things were absolutely wrong.

We'll talk about how well this drug worked, how non-toxic it was,

and in fact, because patients continue on this drug potentially life-long,

in fact, this drug is making quite a bit of money for Novartis,

as it turns out because the drug was patented when it came to my lab,

I don't see any revenue, either to my laboratory or to my university, but that's actually a separate story.

Once we were able to convince the drug company, though, and this took a couple of years,

we ultimately did begin phase I clinical trials in June of 1998.

Now, these were very typical phase I clinical trials.

It was a dose escalation starting with very, very low doses and then as we saw that these lower doses were safe,

we began to increase the dose stepwise and ultimately went up to doses of a hundred milligrams.

Now, as it turned out, the biggest capsule size we had was 100 milligrams,

so at 1000 mg, patients were taking 10 pills once a day,

and we almost got to sort of maximal pill tolerance per day.

But in terms of side effects, even at a thousand milligrams, we didn't reach a maximally tolerated dose,

which was actually the intent of the phase I trial, was to define a maximally tolerated dose.

But the reality is is that long before we reached a thousand milligrams,

we were seeing significant therapeutic benefits.

So, once we got to 300 milligrams per day and above,

we were seeing significant therapeutic benefits with minimal side effects.

And just to give you an example of what we were seeing,

in chronic phase patients who had failed standard therapy with interferon,

98 percent, in fact, that was 53 out of 54 patients, had their blood counts return to completely normal,

a so-called complete hematologic response, or CHR.

And with one year of follow-up, only one of those patients relapsed.

And in blast crisis patients, we've historically had a response rate of less than 5 to 10 percent,

to high-dose chemotherapy, we saw close to a 60 percent response rate.

Eighteen percent of those were durable at one year duration.

So, just to give you an example of our five hundred milligram dose cohort,

this is our chronic phase cohort. The line at 10 represents a normal white blood count.

And what you can see is that all of our patients come in with high white blood counts,

anywhere from 20 to 30, even up as high as a hundred thousand.

Within two to three weeks, their white blood count begins to fall, within four to six weeks, it's normal,

and it remains normal throughout the duration of therapy.

And this was typical and shows just how rapidly and reliable our responses were with this drug.

Now, it's said that when you develop a successful drug,

you really only need on patient to tell you that you have a successful drug.

And for me, this was my one patient. And this essentially is a before and after picture.

Now, this is a patient I had been following in my clinic for close to two years.

And I'd been adjusting his dose of a medication called hydrea for his CML

to try to dampen the amplitude of these waves in his white blood count.

Now, the reason I have these blood counts is the patient's wife is an accountant.

And she used to keep track of how well I was doing and she'd come in at this point

and she'd say to me "Dr. Druker, you're really not doing all that well at controlling my husband's blood counts."

And I'd look back at her and I'd say, well, I'm doing the best I can.

And in fact, it had taken me a couple of years to figure out how to control her husband's blood counts.

In April of 1999, we started this patient on 300 milligrams per day of imatinib.

Within three weeks, his blood count returned to normal and by December of that year, it remained normal.

And the reason I don't have blood counts out beyond here is the patient's wife finally conceded

that yes, Dr. Druker, you're doing ok at controlling my husband's leukemia,

and you can continue to manage him.

Now, as it turns out, I generally don't like anecdotes, and neither does the FDA.

So, we had to go to much larger phase II studies.

And in our phase II studies, these included chronic phase patients who had failed standard therapy of interferon,

as well as accelerated phase and blast crisis.

And pretty much the results that we saw in the phase II studies were the same was we saw in the phase I study.

So, in terms of return of blood counts to normal, in chronic phase patients who had failed interferon,

95 percent of patients had their blood counts return to normal.

In blast crisis, about half of the patients had their blood counts return to normal

and accelerated phase was somewhere in between.

So, now, these are obviously much larger numbers. We enrolled 450 patients in chronic phase,

and about another five hundred patients in accelerated phase and blast crisis combined.

When we also, if we looked at the disappearance of the Philadelphic chromosome,

a so-called major cytogenetic response where we can't detect the Philadelphic chromosome

or it's present in less than 35 percent of metaphases,

again, we saw very high responses. Sixty percent in chronic phase patients who had failed interferon,

and even 16 percent in blast crisis. And historically, it was incredibly rare to see a cytogenetic response,

or lowering of the number of metaphases that had the Philadelphic chromosome in a blast crisis patient.

So, it was pretty clear from these clinical trials that we had something that was unique.

Now, these phase II trials are what ultimately led to FDA approval of this drug,

in less than three years from our initiation of clinical trial and with a six-week review period at the FDA.

From there, we then moved into randomized studies in newly diagnosed patients.

So, the view in oncology is you start with the more advanced phases

and then move therapy up into newly diagnosed patients.

And this was a head to head comparison to standard therapy and it was an enormous trial.

A hundred and seventy-seven centers in 16 countries, over a thousand patients enrolled in about a six month period.

And when you think about it, 5,000 patients per year diagnosed in the United States with CML,

over a thousand patients enrolled in a 6 month period, that's close to 20 percent of all newly diagnosed patients,

and you can immediately tell why it had to go to so many centers in so many countries.

But this is still the most rapidly accrued clinical trial in leukemia in perhaps even any oncologic disease.

Half the patients got imatinib in 400 milligrams per day as a pill

and half the patients got interferon as a subcutaneous injection,

plus another drug called Ara-C.

Now, I'll spare you all the typical clinical trials detail,

and just tell you that these 553 patients assigned to either arm were well matched

for any possible prognostic factor you could imagine.

And I'll just give you the bottom line results.

So, if we just look at the return of blood counts to normal,

imatinib, almost everybody, 97 percent, interferon plus Ara-C, about 69 percent.

If we next look at the disappearance of the Philadelphic chromosome,

this is known as a complete cytogenetic response, no Philadelphic chromosome detected in any metaphases,

three-quarters of the patients randomized to imatinib achieved that level of response

and a pretty typical 14 percent of patients randomized to interferon.

So, imatinib, five times better.

If we now look at tolerance, how well was this drug tolerated,

one-third of patients randomized to interferon had to discontinue therapy.

And if you think about why, think about the worst case of a cold or flu you've ever had.

Fevers, chills, muscle aches, wanting to stay in bed all day, no energy, depression,

that's what happens to our patients on interferon and the reason is, is that when you get a cold or the flu,

your body produces interferon. And for patients with CML that were treated with interferon,

we're giving them a massive dose of interferon every single day for possibly the rest of their life.

But in contrast, imatinib, only three percent of patients discontinued therapy for side effects.

I should also mention that if you use statistics on all of these three findings,

all the p-values are less than 0.001.

Now, we have five years of follow-up on these patients, who initially received imatinib.

And if you look at their overall survival, the overall survival is 90 percent at five years.

If you just look at deaths specifically related to CML, the CML-specific survival is actually 95 percent.

So, earlier on, I told you that the median survival was somewhere around 5 years,

now we've completed changed the prognosis for this disease with a 90 percent or better five year survival.

If we now look at relapses or disease progression,

only six to seven percent of patients have progressed to accelerated phase or blast crisis.

Again, historically, the average duration of the chronic phase was around four to five years,

and now, at five years, 93 percent of patients have not gone into accelerated phase or blast crisis.

Overall, about 17 percent of patients have had some indication of disease progression.

This includes the seven percent of patients who progressed to accelerated phase or blast crisis,

but also includes patients who've had their blood counts become abnormal again,

and patients who've lost their complete cytogenetic response.

But, one of the things you really can't glean from the yearly relapse curves

is the fact that the yearly risk of relapse is actually decreasing over time.

So, if you look, there's actually a peak of relapses in the first and second year

for either progression to accelerated phase or blast crisis, or any event, including loss of a complete cytogenetic response,

or loss of complete hematologic response.

But in year three, the risk of relapse goes down, year four and five it continues down,

and so that in year five, it's less than one percent overall.

And what that means, and what we hope if this trend continues that means,

that the duration of this disease will be significantly prolonged if patients make it beyond the, say the second or third year,

the risk of relapse really becomes quite negligible,

and it may well mean that our relapse curves at five or ten years may actually begin to plateau,

and that would certainly be very good news for patients with this disease who are on therapy currently.

So, to summarize our chronic myeloid leukemia trials,

we have a drug that yields a very high response rate with minimal toxicity in all phases of CML.

Our chronic phase patients are achieving very durable responses,

with a close to 90 percent five year survival.

But as you saw in advanced phase, resistance is relatively common

and that is certainly one of the problems that needs to be addressed.

The Description of Brian Druker (OHSU) Part 1: Imatinib (Gleevec): A Targeted Cancer Therapy