Tag Archives: nilotinib

NICE deny Leukaemia Patients Life Saving Cancer Drugs

NICE (National Institute for Health and Clinical Excellence) have recently returned their provisional results on Nilotinib and Dasatinib as alternative therapy for Imatinib (Glivec / Gleevec) intolerant patients. Basically they are denying these patients a chance of life on what I can see as purely a cost issue.

The CML Support Group has set up an Online Petition against this which I implore you to sign.

A representative of the CML Support Group said ‘Patients are angry, frightened and very frustrated by the provisional recommendation by the NICE appraisal committee- a recommendation that seems to us to have much more to do with cost cutting than with a rational appraisal of two highly effective and innovative therapies.

If the recommendation is upheld, and NHS funding of these therapies is refused in cases of imatinib intolerance, it will undoubtedly cost lives. It is a shocking prospect that UK citizens, who prove to be intolerant to standard dose imatinib (Glivec) will be denied access to such effective and life-saving alternatives. Clinicians will find themselves unable to offer these therapies to their patients in the knowledge that expert clinicians in Germany, France, the Netherlands and other EU countries, will continue to treat CML patients with these life-saving therapies. NICE have clearly acknowledged that both nilotinib (Tasigna) and dasatinib (Sprycel) are clinically effective and very well tolerated oral therapies.

It is difficult to understand why NICE have singled out imatinib (Glivec) intolerant patients in chronic or accelerated phase CML (but not blast phase) for a provisional recommendation that they alone should be denied access to these life-saving therapies. As a consequence, this group of patients, who currently represent around 30-40 British citizens of all ages, will suffer an appalling injustice that puts them at great risk of dying from acute (blast) phase CML.

We call upon the Secretary of State for Health to ensure all CML patients intolerant of Glivec (imatinib) have equality of access to these life-saving drugs.

This reminds me of the issues I had back in 2001 when trying to get Glivec. You can read the outcome on My Leukaemia Story.

It is difficult to put into words how this makes you feel as a patient. Jed’s story on the video below sum’s up the issues and feelings and I strongly recommend watching the short clip.

This also has potential significance for me personally. If I was to become intolerant to Glivec then I would effectively be denied the opportunity to try what is showing to be a successful alternative. For me it is my Plan B.

I (and all other CML patients) would appreciate if you could show your support by signing the petition:

Sign The Online Petition By Clicking This Link!

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Filed under chronic myeloid leukaemia, gleevec, glivec, imatinib, leukaemia, NICE

CML – NICE – epetition response – Dasatinib (DS) & Nilotinib (NL)

Just a quick post to show the reply to 10 Downing Street’s latest reply to the Dasatinib and Nilotinib petiton and challenge to acceptance as 2nd line therapy for resistant / intolerant Imatinib (aka Glivec, Gleevec).

I am not going to comment directly here at this stage, as in my opinion there are huge flaws in the study for the judgement, however we await the full reply and go from there.

Direct quote from 10 Downing Street:

We received a petition asking:

“We the undersigned petition the Prime Minister to overturn the decision by NICE to refuse 2nd generation life saving drugs to CML patients.”

Details of Petition:

“Chronic myeloid leukaemia is a form of blood cancer. The current treatment is Imatinib (IM).

Approx. 40% of individuals may display resistance to IM. Dasatinib (DS) & Nilotinib (NL) are licensed for the treatment of adults with chronic & accelerated phase CML with resistance or intolerance to IM.

DS is also effective for Blast Crisis CML. Both received approval by the FDA & EMEA.

NICE do not accept the evidence supplied in the initial report, as they consider open label, non blinded trial designs seriously flawed.

Cost of supply is the issue. We are urging NICE to reassess their decision NOT TO fund the use of these EFFECTIVE treatments on the basis of cost – without the need for 4 arm (DS, NL, high dose IM) double blind randomised studies including a control group receiving ‘best supportive care’ – allowing none of them to crossover and no dose escalations according to how they respond.

The NICE assumed average age for CML is 60. Would you accept such a trial would be morally/ethically correct if it was aimed at young children with CML? What if your National Insurance scheme now doesn’t treat you with the best drugs because the cost is considered too high?.”

Read the Government’s response

In response to the concerns that many people have about the availability of dasatinib and nilotinib for the treatment of chronic myeloid leukaemia, the Department of Health should stress that the National Institute for Health and Clinical Excellence (NICE) has not yet published final guidance on the use of dasatinib and nilotinib.

NICE has recently issued draft guidance that does not recommend the use of dasatinib and nilotinib for the treatment of chronic myeloid leukaemia and registered stakeholders had until 7 December 2009 to submit comments.

NICE’s Appraisal Committee is considering the responses to the consultation and the Institute currently expects to issue its final guidance to the NHS in April 2010.

NICE is an independent body, which makes decisions on the clinical and cost effectiveness of products based on a thorough assessment of the available evidence involving extensive consultation with stakeholders and in the context of a finite NHS budget.

Some of these treatments cost thousands of pounds, so NHS bodies must find a balance between funding expensive drugs for a limited number of patients and providing services and treatments that will benefit many other people.

The Department recognises that the Institute’s decisions have serious implications for patients and their carers. These are very difficult decisions and they are made only after careful consideration.

It would therefore not be appropriate for Ministers or officials to intervene in an ongoing appraisal. However, several patient groups are registered stakeholders in this appraisal and concerned parties may wish to raise concerns about NICE’s guidance with one of these organisations. Details of stakeholder organisations can be found at: http://www.guidance.nice.org.uk/TA/Wave17/18

Where NICE guidance is not yet available for a treatment, the NHS Constitution gives patients a right to expect local funding decisions on the availability of drugs and treatments to be made rationally and on the basis of the available evidence. NHS organisations are also required to have processes in place for the consideration of exceptional cases, even where NICE has not recommended a particular drug or treatment.”

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Filed under chronic myeloid leukaemia, gleevec, glivec, imatinib, leukaemia, leukaemia research

Understanding CML, Glivec, PCR results and where I fit in.

I have many questions asked around what is Chronic Myeloid Leukaemia (CML), Glivec (aka. Gleevec, Imatinib, STI571) what are my results and how are they measured.

Dr Brian J Druker whom was instrumental in the development of Glivec did a fantastic webcast in December 2008 which explains everything in laymans terms that the majority of people can understand.

The full webcast can be seen here and I would strongly recommend any CML patients and carers/family to watch in full.

In order for those of you that have asked where I fit in below is a transcript from Dr Brian J Druker on part of the webcast on http://www.cancereducation.com

It is word for word and uses the American spelling for leukaemia – leukemia. I feel it should be read as it was spoken by Dr Druker.

To see where I fit in here are a few specifics about me not mentioned in My Leukaemia Story My Leukaemia Story which will make more sense when watching the webcast or reading the transcript below.

• I am monitored on PCR
• I am now tested every 6 months
• It took me 1 year on Imatinib (aka Gleevec, Glivec, STI571) to get zero on cytogenetic monitoring (bone marrow sample)
• It took a further year to get a PCR ‘3 log’ reduction.
• Since then my PCR ‘bounces’ around 0% to 0.05% which is extremely stable.
• My last PCR results was 0.03%
• I have the ‘3 log’ reduction
• I am on 400mg Imatinib per day and have been since Aug 2001.

So here’s Dr Druker’s transcript from ‘Monitoring CML’ part of the webcast:

“What I want to do tonight is talk about what’s new for newly diagnosed patients with chronic myelogenous leukemia (CML), but prior to doing that, I want to give you some background about how we monitor CML and what some of the terms mean.

For those of you who have listened to these teleconferences previously or who have seen me in my clinic, this is going to be old hat for you, but those of you that are new to the program or are newly diagnosed, I really want to spend just 5 minutes getting us to speak a common language because as you’ll hear throughout my comments and throughout Dr. Shah’s comments, it’s important that we understand what our goals of therapy are, and to understand what the goals of therapy are you kind of need to know a little bit of the insider’s doctor’s language.

So I’ll walk you through that relatively slowly and carefully.

How do we monitor CML?

Clearly, we can monitor blood counts. We can also test for the presence of the abnormal chromosome that marks leukemia cells, the Philadelphia chromosome.

We can look for the Philadelphia chromosome either through cytogenetics, it can be done on bone marrow, or we’ll look at 20 dividing cells.

We can also use FISH (fluorescence in situ hybridization), either on blood or bone marrow, where we look at 200 cells, either dividing or non-dividing, or a polymerase chain reaction (PCR) where we can look for traces of leukemia in as many as a million cells.

So, let’s talk about this in a slightly different way, and let’s think about this in terms of numbers of leukemia cells. The ideal would be not to have any leukemia cells.

If you didn’t have any leukemia cells, you don’t have leukemia, and if we can ever get you to that point, we can say that you’re cured.

At diagnosis, most people with CML will have a white count of 50,000 to 500,000. A normal white count should be 5,000 to 10,000.

That’s anywhere between 5 to 50 times the upper limit of normal. In a normal bone marrow, there are 1 trillion cells.

Now that sounds like a big number, but that’s how many normal cells are in a normal bone marrow. If the bone marrow’s been taken over by leukemia, you have as many as 1 trillion leukemia cells. That may sound like a huge number, but that’s how many cells a normal bone marrow has, and now your bone marrow has leukemia.

The first goal of therapy is to get your white count down to normal. If you have a normal white count, we would call that a complete hematologic response. So a complete hematologic response simply means a normal white blood count.

Now the problem with that is that we really don’t know how much lower you’ve gone, how close you are to zero. We’ve only reduced the number of leukemia cells by maybe 10-fold, perhaps down only to 100 billion leukemia cells. So we’ve got to do much more sensitive testing, and this is where cytogenetics comes in.

This looks for the abnormal chromosome. This abnormal chromosome, which marks the leukemia cells, comes about because 2 chromosomes, chromosomes 9 and 22, exchange pieces, and you end up with a short chromosome 22, which is called the Philadelphia chromosome, and a longer chromosome 9.

It’s this short Philadelphia chromosome that we can look for in the bone marrow that marks leukemia cells and is actually what causes leukemia. This is what we look for in cytogenetics. We look for the presence of the Philadelphia chromosome.

As I mentioned, we look at 20 cells. Typically, when someone is diagnosed, all 20 of their bone marrow cells will have the Philadelphia chromosome. So it’ll be 20 out of 20 Philadelphia chromosome positive.

Now when somebody has a normal white blood count, what if they still were 20 out of 20 Philadelphia chromosome positive?

What that tells us is that most of their blood cells are still leukemic despite having a normal white blood count, and our estimates would be that that patient has 100 billion leukemia cells left.

Now, the reality is it’s better to have a normal white count than a white count of 500,000, but you could still be left with a lot of leukemia cells.

So the next goal of therapy would be to try to get somebody down to 0 out of 20 Philadelphia chromosome positive, also called Philadelphia chromosome negative, or a complete cytogenetic response. All those terms mean the same thing. It just means we’ve gotten you to Philadelphia chromosome negative.

In reality, we’ve only looked at 20 cells. A normal bone marrow has a trillion. We’ve just looked at a drop in the bucket. We’ve got to get much more sensitive tests if we’re going to figure out how well controlled somebody’s disease is.

Again, however, it’s far better to be Philadelphia chromosome negative than Philadelphia chromosome positive. So we need a more sensitive test known as PCR.

PCR testing is, for those of you that follow some of these crime scene dramas, the cops go to the scene of the crime, they scrape a piece of blood and figure out who did it. We can sort of do the same thing with a test tube, a vial of blood.

We can look for a trace of leukemia in that vial of blood. So with PCR testing, we can amplify a signal, and we can see 1 leukemia cell in between 1,000 to 1 million normal cells.

Now this PCR testing can be qualitative. It simply gives you a positive or negative. It tells you if this Philadelphia chromosome abnormality, which we’ll now call BCR-ABL, is present or not present. We can also do a quantitative test where it gives us an estimate of the number of leukemia cells.

So if we put this back on our graph, the reality is that we now can go from 1 trillion cells down to 1 million leukemia cells, but we have to make a couple of points here.

First, if you do an equivalence ratio, 1 in 1 million is equivalent to 1 million in 1 trillion. So PCR undetectable could still mean you have 1 million leukemia cells left. It doesn’t mean cured, and it also means that we can’t do anything more sensitive to look for lower levels of leukemia.

So PCR undetectable or PCR negative doesn’t mean cured. It just means the lowest level we can identify.

The second point is that about 80% of patients treated with imatinib will be between Philadelphia chromosome negative or complete cytogenetic response and PCR undetectable.

Most people will be there. The only way we can monitor patients in this range, where the majority of people are, is through PCR testing.

So let’s look at this graph, looking at PCR values, and here I’ve taken what’s now known, on the left-hand side, something called the International Scale where newly diagnosed patients arbitrarily would have a value of 100, and I’ve done 10-fold reductions, and you can see on the very far right we have a 3-log reduction. That just means 1,000-fold reduction in the number of leukemia cells, and that has some prognostic importance.

We can make a couple of other points.

First, I’ve shown this on a quantitative scale, meaning the quantitative PCR that gives us a number. If we did a qualitative PCRthat just said present or absent, all of these values would be positive. You couldn’t tell the difference between a newly diagnosed patient who would have a value of 100 and a very, very well-controlled patient, who would have a value of 1, which would likely be a complete cytogenetic response, 0.1 or even lower. So the reality is this quantitative PCR gives us a far better insight into how well controlled people’s leukemia is.

Second, clearly quantitative monitoring is preferred. It gives us an indication of where people are. The problem, though, is that different labs will give you different results. If you come to my hospital in Oregon or Dr. Neil Shah’s hospital in San Francisco, we’ll give you different results. We are working on standardization so that you can go anywhere in the world and have the same testing done and the same results done, but unfortunately we don’t yet have a standardized test. Until then, my
recommendation is that you send your samples to the same lab so that you can follow a trend.

For those of you who are interested, Novartis has set up a program called the CML Alliance™ and they currently use 2 labs. If you’re currently not being done at one of these labs, I would urge you to think about working with your physician through the CML Alliance, to have your testing done routinely at a standardized testing laboratory.

A third point about monitoring is that negative results also depend on the quality of the lab and the quality of the sample. The sensitivities vary from lab to lab, from 1 in 1,000 to 1 in 1 million, and so negative at 1 in 1,000 is not as good as negative at 1 in 1 million. Different labs, again, will have different results.

What do I consider a good response?

There’s a 3-log reduction. Any time you get it, it is a great place to be. (That’s me – Harvey)

Six months, 1 year, 2 years, that’s a great place to be.

The risk of relapse is a half percent per year, and it decreases over time. So at a half percent per year, that means that at 10 years, 5% of people in that category would relapse.

With a complete cytogenetic response to Philadelphia chromosome negative, there is a 2% risk of relapse per year, and by year 4 of maintaining that response, it declines to a half percent per year. So my view is that a stable complete cytogenetic response is equal to this 3-log reduction.

What about when a change in therapy should be considered?

Certainly somebody who doesn’t get their blood count to normal in 3 months, I would certainly consider switching therapy. I would also consider switching therapy for somebody who’s greater than 95% Philadelphia chromosome positive after 6 months or 35% positive after 1 year of imatinib therapy.

During the discussion, Dr. Shah and I can talk a little bit about when to get a complete cytogenetic response, when to get this 3-log, and there’s currently a fair bit of individual variation between physicians about what to do with those patients.

What about the dose of imatinib?

At the recent American Society of Hematology (ASH) meeting, there were 2 random studies that looked at 400 mg versus 800 mg and showed no differences in response.

There was, however, a trend for fast responses in patients who could maintain higher dose therapy, and there was also a suggestion that people with high drug levels of imatinib may be more likely to get this 3-log reduction but at the expense of having more toxicity.

The point here is that early on when people did non randomized studies, they just looked at 800 mg and compared historical data on 400 mg, but 800 mg looked a lot better. When you did a head-to-head comparison withidentical comparison groups, no significant difference was seen. It points out the importance of doing these randomized controlled studies to guide therapy.

Should we be monitoring drug levels?

Certainly, in patients with less than optimal responses and severe toxicity, we absolutely would recommend monitoring drug levels, and as we look at the emergence of this new data about higher drug levels resulting in better responses, we’re seriously considering that newly diagnosed patients should have a spot drug-level check. We might be able to adjust their therapy, but also, I think we still need some more data.

The 2 new drugs that Dr. Shah will talk about that are showing significant activity in relapsed patients have now been tried in newly diagnosed patients.

Once again, the early data suggests higher response rates and faster responses. This early data looks similar and maybe even a little bit better than when imatinib at 800 mg was examined in this group of patients.

It’s my view that we wouldn’t change therapy until we do a head-to-head comparison looking at imatinib versus one of these 2 new drugs, but clearly we need to do these studies, and if these drugs are better, we need to change our treatment recommendations based on these randomized studies.

What about stopping imatinib?

Many patients are undetectable by PCR.

There were 2 studies reported at the ASH meeting that were very small, with follow-up averaging around 6 months, and for a few patients, a couple of years.

What was interesting is that a few patients, maybe 5% or 10%, haven’t had their PCRs become positive. In reality, there are very few patients who are past 1 year on these studies.

Many of the patients who haven’t relapsed had previously received interferon but, in fact, there were some patients who had only received imatinib.

Their PCRs were negative for a couple of years, and they haven’t relapsed. It’s absolutely intriguing to think that there may be a small subset of patients for whom we could stop imatinib, but we clearly need way more follow-up and more patients on these types of studies.

What about lowering the dose of imatinib?

Certainly, I would consider lowering the dose for patients who have had a least a 3-log reduction, have a very low risk of relapse, and maintain this for a couple of years.

I would also consider lowering the dose for people with a complete cytogenetic response who have maintained that for at least 4 years, when I know their risk of relapse is extremely low, and for anyone for whom imatinib is affecting the quality of their life.

How would I do this?

First of all, I’d look to see what doses did it take to get them to their response. If the needed 800 mg to get to a complete cytogenetic response, I’m not going to be eager to lower their dose.

If we started them on 800 mg, and they got a very rapid response, I might actually think about lowering them. I would absolutely recommend levels and not reducing below a drug level of 500 ng/mL.

That’s typically achieved with imatinib doses of 300 mg to 400 mg per day. I would be monitoring PCR very closely every 3 months, sometimes even more often, and we typically have lowered the doses very gradually, not making rapid changes. If the PCR goes back up, we can again increase the dose.

What conclusions should we take away from this?

In our practice, imatinib at 400 mg per day is still the standard of therapy. There are ongoing randomized studies that are comparing imatinib to nilotinib (Tasigna®) for newly diagnosed patients who eagerly await the results of those studies, and we hope within another year or 2, we’ll have those results.

We clearly need to do a better job of identifying which patients are least likely to respond or are at the highest risk of relapse.

These might be patients for whom more intense drug level monitoring would be in order. In addition, we have other tests in development that may help us identify which patients should be treated with some of the new drugs or higher dose therapies.

What about the future?

Although I mentioned some intriguing results about stopping imatinib, it’s my view that these are inconclusive, and it’s my current view that the current drugs are unlikely to cure CML as a single agent, and we absolutely need more research into methods into eradicating remaining CML cells.”

So if you have read this far I hope it helps, and I still recommend watching the full webcast :



Filed under chronic myeloid leukaemia, gleevec, glivec, imatinib, leukaemia, leukaemia & lymphoma research