Biological therapies - targeted cancer drugs for leukaemia
Biological therapies - targeted cancer drugs are derived from, or target substances that occur naturally in the body. They have been designed or modified in the laboratory to attack or control particular types of cancer cells. Because they are targeted, they have a different mechanism of action compared to traditional “cytotoxic” chemotherapy, and side effects like hair loss are less common. Targeted cancer drugs may be used together with other treatments for various kinds of leukaemia but for chronic myeloid leukaemia (CML) it is used alone as first line treatment.
Tyrosine Kinase Inhibitors (TKIs)
Tyrosine Kinase Inhibitors block the action of enzymes called tyrosine kinases. These enzymes may be too active or found at high levels in some types of leukaemia, and blocking them may help keep cancer cells from growing.
In CML, the uncontrolled multiplication of white blood cells is a caused by a growth signal (tyrosine kinases) being permanently switched to “on”. The biological drug imatinib (Glivec) attacks the growth signal, stopping the uncontrolled growth, producing remission. Following development and clinical trials during the 1990s, imatinib came into routine use in Britain in 2002, revolutionising the treatment and prognosis of CML. People we spoke to had been among the first to have it in the UK. Some initially had it in a clinical trial and continued taking it afterwards. Another woman obtained the drug outside a trial but before it was routinely used in the NHS.
She is a Human Resources Consultant. She is married with no children. Ethnic background: Asian.
And so that’s how it’s been. Well, initially interferon and since then my drugs have changed. In 2000 I was lucky enough to be part of the Glivec trial, or the imatinib trial as it was known at the time. I was one of the first or second, one of the sort of initial group of patients who were on trial and luckily it worked very well for me and since then I’ve been on Glivec. And yes, I’m doing fine so things are I think nicely balanced out at this stage. Yes, so it’s not been a very difficult ride. It has had some impact on work and on family but overall I would say I’ve been lucky with the way things have turned out for me.
Imatinib (Glivec) is taken daily as a single capsule or tablet, or four smaller tablets. Most people took it with their evening meal to avoid nausea. Having felt sick after taking it in the mornings, one woman preferred to take it at bedtime. Most people had few or mild side-effects, but Elizabeth at first reacted badly to the drug, was hospitalised and had to stop and restart it repeatedly before achieving remission (see ‘Unwanted effects of treatments’).
Chanelle is a project manager. She lives with her partner and has no children. Ethnic background: White British.
Can you tell me a bit more about the Glivec - how that’s administered and how often you have it?
When you were having it originally and whether it’s different now.
Yeah. When I first started. Glivec is in tablet form and when I was first taking it, it was four tablets, which made up four hundred milligrams. And now I take a single 400 milligram tablet. And that’s taken once a day in the evening after my evening meal. And that’s just all you need to do really.
Right. So every day of your life.
Yes, every day. Yeah.
And how do you feel about having to do that?
I don’t actually think it’s too onerous really, it’s kind of just something that’s so automatic to me now. And I think compared to having to inject yourself and what have you. I mean I guess it’s all relative, I suppose if I’d started taking tablets every day then I would have thought this is more of a pain really because I’ve got to remember to take it. But it’s such an easy option for me compared to what I started on that it doesn’t actually bother me. It doesn’t bother me and I just don’t forget it. It’s just second nature.
I think so many people take medication for different things, bits and pieces they have to do everyday anyway, that it really doesn’t bother me at all. No, I don’t find that a problem.
So what is the likelihood of it coming back?
It’s very difficult to say because not enough is known about the drug that I’m taking. I think that there is always a real possibility that the drugs that I’m taking will stop working, that you will develop an intolerance and then the drugs will stop being effective. And that’s something that I have to keep in mind because, as I said, it’s such a young treatment. It’s been around under ten years.
So the follow up on it is not massive and that’s something I do have to keep in mind. But what I try to keep in mind is whilst there is the possibility that this is not a forever drug there is also a very good possibility that it is a forever drug. And it used to be something that I worried about a lot but now I’m happy to be among the group of people that are proving that this will work or it won’t work. I mean whilst it doesn’t work for different people, for those it does work for there is that possibility that it could be a lifetime’s control. But I mean I do try and keep that in mind that there might come a day when I have to seek other options.
Imatinib is also used as a treatment for people with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) and has improved the prognosis of these patients when it is combined with chemotherapy. Bone marrow transplant remains the recommended treatment for this disease.
Other Tyrosine Kinase Inhibitors for CML
There are other Tyrosine Kinase Inhibitors that are similar to imatinib (Glivec); dasatinib (Sprycel) and nilotinib (Tasigna), and can be given when people with CML do not respond, become resistant to imatinib or have too many side effects on imatinib. Ponatinib (Iclusig) or bosutinib (Bosulif) are newer Tyrosine Kinase Inhibitors that target different proteins. You might have these drugs as part of a clinical trial or through the Cancer Drugs Fund.
B-cell signalling inhibitors
In chronic lymphocytic leukaemia (CLL) the cells have proteins on the outside called B-cell receptors (BCRs). When a protein binds to a BCR it sends a signal to the cell to survive. CLL cells are very sensitive to BCR signals, which means the bone marrow produces too many and these fill up the bone marrow and stop it from producing normal healthy cells. B-cell signalling inhibitors block or inhibit the survival signal in CLL cells, allowing them to be die more quickly. Ibrutinib (Imbruvica) and Idelalisib (Zydelig) are B-cell signalling inhibitors used in the treatment of CLL.
Monoclonal antibodies - Immunotherapy
The body makes antibodies in response to infection, enabling the immune system to recognise infections it has met before and deal with them quickly. Monoclonal antibodies made in a laboratory can recognise particular types of cancer cells and make the immune system attack them. Types of monoclonal antibodies used for leukaemia are rituximab (Rituxan), alemtuzamab (Campath 1H), gemtuzumab (Mylotarg), ofatumumab (Arzerra), obinutuzumab (Gazyvaro).
This targets a protein called CD20 on the surface of B lymphocytes (a type of white blood cell) and destroys them. It is given intravenously and is used mainly to treat non-Hodgkin’s lymphoma but now also CLL in combination with chemotherapy (FCR). Rituximab may also be used to treat B-cell ALL.One man with chronic lymphocytic leukaemia (CLL) was given it after his lymphocytes attacked his red blood cells causing them to break down (haemolysis). This autoimmune haemolytic anaemia (AIHA) is a complication of CLL. Later he received another monoclonal antibody, alemtuzumab, as part of preparation for a stem cell transplant.
Michael is a semi-retired university lecturer. He is married with 3 children aged 15, 17 and 25. Ethnic background: White British.
And then they found a, I think it was a type of rituximab, I think it is, and they use that, and they were able, I don’t understand the science behind it, but apparently it can sometimes work to solve the problem [of haemolysis]. And gradually my counts, my red cell counts, having gone as low as 4 - and the normal is 12, 13 - started to increase slowly. But I was, as I said, I was three weeks in hospital and when I came out it took another couple of months really before I was in any respects better and able to cope. So I was in bed and at home quite a bit.
And then they tried me on something called, I carried on with the rituximab after I came out and that certainly helped. And then they tried something called Campath, their plan was that they would try and get a grip on the disease, try and flatten it as much as they could, suppress it as much as they could and then go for an autologous transplant, which is basically where they take the cells, my own cells and then put them back into me at a later date. And apparently this can work, stem cells.
That was the plan and as the first stage in that they gave me this Campath and it had a miraculous effect on my counts. It brought them right down to, you know, the white cell count very low, right down to the low end of normal. And it sort of stayed there and I thought this was absolutely terrific. And so we were now, this was in November 2005. They weren’t able to give me all the Campath treatment because there’s a reaction that you sometimes get, and I got the reaction and they have to stop the treatment if you get that, but I’d had quite a bit of it, probably about forty per cent of it.
And then I felt all right. My counts were pretty low and now there was a big debate, you know, how long would it last? Would the counts come up again? Was I cured?, if that’s not a meaningless word in this context, because they never actually ever tell you you’re cured. What was going to happen?
Okay. So how was the Campath administered? Was that intravenous or was that tablets?
It was intravenous. I was treated as an outpatient. I had to go, it was quite intensive, I think I was maybe three, perhaps four times a week, and it took most of the day. It was quite time consuming but at least I wasn’t an inpatient. So that was good.
And what’s the rituximab like? How’s that administered? What’s it like having it?
That was also administered intravenously and again that was quite time consuming. And you often feel, actually I think it was the Campath that caused, you know, to prevent a skin reaction you have to have some Piriton (chlorphenamine), and that makes you feel drowsy, so you have to wait quite a while before you can drive home afterwards. So the whole day really is in a sense wiped out. And yes, rituximab was also administered intravenously.
Glyn was given alemtuzumab after his CLL had not responded to chemotherapy. He went to hospital three days each week and initially was given the drug intravenously, then by injection under the skin (subcutaneously).
Gemtuzumab (Mylotarg) is a combination of a monoclonal antibody and a chemotherapy drug. The ending '-mab' in the name indicates that it is a monoclonal antibody. It attaches to a protein on the surface of leukaemia cells thereby destroying them without harming normal cells. Some people with acute myeloid leukaemia (AML) were given gemtuzumab (Mylotarg) as part of a clinical trial.
Lenalidomide can block the growth of blood vessels and so prevent cancers spreading. It is a new drug whose action is not fully understood and it is not routinely used in leukaemia, but it is used in myeloma, another form of bone marrow cancer. Glyn’s doctors applied to the then local Primary Care Trust for permission to give him lenalidomide after chemotherapy and antibody therapy had not worked. The drug is taken as capsules at home and Glyn had a slight upset stomach at first. He had no other side effects and his CLL is now in remission.
Glyn is a retired management accountant. He is married with two adult children. Ethnic background: White English.
And so when it came through we were over the moon that they were going to start me on this, and especially as we found out when we went down to the pharmacy to get this drug and they said, “Oh, no we don’t keep this drug”, you know, “We’ve got to get it from the manufacturer.” And I said, “What? Won’t they give you stock?” “Oh, no.” They said, “At £4000 a box there’s no way they’ll let you have it here.” And I take one every day whereas the list of treatments on the thing is one for 21 days and a week off. But I have them all the time because they’re more effective doing that.
So they’ve been absolutely great and in fact they gave me a bone marrow test half way through the year and that showed really nothing in it didn’t it? It was really good.
But my red bloods are just going stronger and stronger and stronger and my white cells are going up now, my platelets are going up. What’s the other one?
Glyn' Neutrophils are increasing.
And so that’s going really well on that and then when we went in November last time we saw him, when he said, “You even appear to be getting some immune system back now.” So that is absolutely marvellous we feel. So we’re really over the moon with that and so this is what I want to let people know really, that it really seems to be working so perfectly for me.
So the Revlimid is tablets is it?
You just take one a day?
Glyn' Yes, I just take one a day. Only 10 milligrams. I started from 5 for a short while, but I’m up to 10. They do go up to 25 apparently but I’m stuck, given me 20, on tens.
And do they give you any side-effects?
Glyn' No, none at all. I haven’t had anything.
Pat' They can do. We were given a list of things to look for and to do. One of them was called tumour flare where all your lymph nodes and that can swell up quite dramatically.
Glyn' And they really were quite concerned about those weren’t they?
Pat' But they gave us a leaflet and there’s also the leaflet in the box that tells you what to look for, and they gave us contact phone numbers to ring if we were concerned about anything in between appointments. We knew the ward phone number. We knew the day ward phone number. So we had all the information we needed and what to watch for, but touch wood.
Glyn' No, it wasn’t, no.
Pat' You didn’t get anything. One or two things yes, you had a slightly upset stomach and things like that, but they all settled down…
Glyn' …Quite quickly really, yes.
So you’ve been taking that for about a year?
Glyn' Yes, a year now.
Pat' Just a year.
Vaccines have long been used to stimulate the immune system to fight bacteria and viruses and they are now being developed to fight cancer cells in the same way. Elizabeth heard about a trial in the USA of a vaccine to be taken alongside imatinib (Glivec) and got permission from her doctors to take part. She paid for her travel to America but once there the drug company covered all expenses. She had some of her CML cells harvested to tailor the vaccine to her disease before receiving nightly injections of the vaccine. Her white blood cell count dropped temporarily but then rose again.
Elizabeth is a retired NHS administrator. She is married with two adult children. Ethnic background: half French Mauritian, half White British.
During that time there was a trial in the US for a vaccine for CML, and they said that it would probably work on those who had a lowish PCR* and were sort of stuck and not getting anywhere with Glivec. You did not have to abandon your drug, and it was in conjunction with taking Glivec. All expenses paid, put up in equivalent to a Travel Lodge or whatever over there in Connecticut. I knew the first batch, I made friends with the first batch of people who actually were there on the trial and they sort of said, “Yeah, nothing in it really, little injection every night in bed, we’re having a ball going out having fun.” And I thought, “huh, I can do with some of that.” So I thought, “Okay. I’m going.” The team at the hospital in London was saying, “Okay. Go. It can’t do you any harm. We’ll see.”
And my first experience of the US was pretty traumatic because they had to collect my cells in order to manufacture the vaccine. And this was pretty much of a disaster because the person inserting the cannula to actually collect the cells made a big botch up of it. And I put up with everything because to me this was a vaccine and this could work and it was worth doing, and all that really. I came back to London with the whole side of my neck out here because they had to actually insert it in my big sort of vein in my neck because they couldn’t get the right veins in my arms to actually do it. But then they did it in whatever way that obviously I had a massive, massive bleed. I came back here, hospitalised for them to CT scan me and actually see what damage had been done in the US. I could have sued them for a million by now with this but I didn’t. And to me it was an end in sight to all this so, you know, I was willing to walk on hot coals still. Anyway, nothing much happened. It all resolved and I was okay.
Then I went back to the US for three months to actually get a vaccine protocol and there was another few people there with me, you know, leukaemia patients, and we got a great community really, which was really good. I had a great time in Connecticut really, and seeing all the area. I went to New York and did lots of fun things but the vaccine amounted to nothing. I think my PCR* dropped quite considerably at the end of the course but then it came back to the level where it was at. So anyway, great experience. Tried it, didn’t work. Okay, carry on with Glivec really.
*PCR' Polymerase Chain Reaction. A test which looks for genetic changes in cells. It can find one leukaemia cell among a million normal cells.
Tretinoin (Vesanoid; ATRA)
This drug is a form of vitamin A. It is given alongside chemotherapy to people with a type of AML called acute promyelocytic leukaemia (APML). It helps the leukaemic cells to mature normally. Side effects are common but it may be difficult to distinguish them from those caused by chemotherapy.
John is retired. He is married with no children. Ethnic background: White British.
One of the first things they give you is called ATRA (tretinoin), and those are tablets and again they don’t appear to have any side-effects except they beat up abnormal white blood cells. And what they really do is they clear them out of your system. Your system is being smothered with a mass of abnormal cells which is changing the way that you cope with your immune system and so on. And what it does is it clears all those abnormal cells which should have died, it encourages them to leave, which is good. Whether or not the ATRA has a more major effect in treatment I don’t know, but certainly it was something that I was given. But I can remember on two or three occasions having to remind people that I had to be given them.
So did you have that in every course of your treatment or was that just at the beginning or what?
That was just at the beginning. I think there’s a certain amount of ATRA that they can give you, they don’t over do it. But that was that. It was just like I suppose taking an aspirin or something, it was just another tablet to take but it was an important tablet to take. Certainly when I read the protocol it clearly identified that ATRA was something that had to be part of this.
“It’s important not to become pregnant or father a child while taking ATRA, as it may harm the developing baby. It’s important to use effective contraception while taking this drug, and for at least a few months afterwards. Your doctor or nurse will discuss this with you. If you’re already pregnant, ATRA shouldn’t be given if you’re less than 12 weeks pregnant. After 12 weeks, it can be given safely. It’s usually given without chemotherapy, as this is safer for the baby and still effective." (Macmillan Cancer Support 2018)
*CML – Chronic myeloid leukaemia
Last reviewed: December 2018. Last updated: December 2018.
Please use the form below to tell us what you think of the site. We’d love to hear about how we’ve helped you, how we could improve or if you have found something that’s broken on the site. We are a small team but will try to reply as quickly as possible.
Please note that we are unable to accept article submissions or offer medical advice. If you are affected by any of the issues covered on this website and need to talk to someone in confidence, please contact The Samaritans or your Doctor.