17th Congress of EHA, Amsterdam, 14-17 June 2012

Best treatment for chronic lymphocytic leukaemia with 17p deletion

Professor Michael Keating – MD Anderson Cancer Center, Houston, USA

Dr Keating, good to talk with you again about this very important topic – chronic lymphocytic leukaemia, which sometimes doesn’t need treating. So could you start off, I want to ask you about the debate you’ve just been having on 17p deletion, patients with that deletion, but first of all the initial work up for this disease, how do you know who to treat and when to treat?

Basically a lot of patients will have a family of cells that are chronic lymphocytic leukaemia but they’re not growing, they’re just sitting there quietly and you don’t need to do anything about it. Many of these patients have absolutely no symptoms and you’d probably do more harm than good at the present time treating them because you end up damaging their DNA and they don’t do as well. The indication for treatment is if, when the patient comes in, they have very bulky disease, that is they have very big lymph glands of 3-4cm, or they have a very big spleen or their bone marrow is not producing normal blood cells; these are the main indications for treatment.

Then you take action with what, in your case?

It is being debated at the present time as to whether we should have a different approach to patients that are younger than 70 years, which is the average age of diagnosis of CLL, or older patients. The best treatment that we have available at the present time is a combination called FCR, which is fludarabine, cyclophosphamide and rituximab, there’s a lot of interest in bendamustine and rituximab, that’s being investigated in Germany as a comparative clinical trial for front line treatment. Now, both of the studies of FCR and BR only had about 10-15% of patients over the age of 70 in that study so we can’t draw analogies to that, in particular giving strong treatment to patients that are infirm. So there’s a lot of interest now in going back to oral agents with antibodies for the older patient population.

Now some of the patients do very well on treatment but others do not. You’ve just been in a debate specifically about patients with the 17p deletion and how these should be treated, what came out of that?

What came out of that is that we don’t have a very satisfactory treatment at all at the present time in that all of the other types of CLL that we put on treatment have a good response, complete remission rate of 65% or thereabouts. The 17ps have a complete remission rate of only about half of that; their median time to failing their treatment ends up being around about 18 months so that they don’t have these long term controls.

Now, there was a discussion about whether to use FCR, the regimen you were just describing, or to use the monoclonal antibody alemtuzumab and things like allogeneic transplantation. What was the balance of opinion? I know you were talking about FCR.

I think the balance of opinion was that people are nervous about FCR because we know a lot more about it and we know that it doesn’t work terribly well. There are some early studies that are coming out with the use of alemtuzumab with high dose corticosteroids like dexamethasone or methyl prednisolone etc that are getting good early responses but they don’t last very long. So the thought is if you can actually decrease the amount of disease and then take them to an allogeneic stem cell transplant that offers them the chance of cure.

But it must be scary to go onto the prospect of allogeneic transplants in a condition which may well remit.

The 17p deleted group of patients will not remit for long times so that we’re facing the situation where some people have a moderate degree of control but all of them will eventually relapse so that to go on to the potentially curative strategy of a stem cell transplant. All the patients know that that’s a risky procedure but if we confront them with the reality of what to expect if they don’t go on to a stem cell transplant, many of them will opt to take that choice.

But you’ve got some good news on the horizon for the 17p, haven’t you, with the B-cell receptor antagonist and there’s talk also about salvage therapy and what you might do.

I think that the 17p deleted group of patients can also be picked up in a small subset that don’t have 17p deletion on FSH by a mutation in their p53 gene. When you put these patients together it’s probably about 10% of patients up front that will have this abnormality going under treatment; in the salvage situation there’s more like 20-25%. There has been data that’s presented at the meeting this time on a drug called ibrutinib which is otherwise known as PCI32765, it’s given as an oral medication, it dramatically shrinks lymph glands down, patients feel better in a very short period of time and their blood counts improve.

And that’s particularly or specifically patients with the 17p?

No, it’s on every group of patients but in the past we had no effective treatment for the 17ps so it’s now getting the same sort of results as the other chromosome abnormality patients.

What might be the clinical implications if these early studies are fulfilled by bigger ones?

At the moment this is so well tolerated and the marrow production and lymph gland reduction is so good that I think that there will be studies as to how long you can control these patients just with this treatment; there will be studies now where you combine them with monoclonal antibodies such as rituximab, or MabThera in Europe; there are studies that are being put in place in combination with other chemotherapy drugs and they’re all showing very promising results with very good tolerance.

Do you see this new approach perhaps moving to earlier in the disease? Is that pushing it too far at the moment?

No, I don’t think it is pushing it too far because we know that as time evolves patients get more and more genetic abnormalities. The reasons for not treating early up until this time has been that we had regimens that were too damaging to the immune system and the DNA of other cells. So the question of are you causing second malignancies, are you suppressing the immune system too much etc, so the risk-benefit was always considered to be in favour of watch and wait. Now you have treatment programmes which are not doing this damage so is it better to control the disease early rather than waiting until the patients really need treatment because they’re sick?

Now the busy cancer doctor needs to be very clear-sighted on all of these issues. Could you give, just 1,2,3, simple guidelines, very briefly, to put us in the picture now.

The guidelines at the present time are that you should only initiate treatment in patients that have the indication for treatment that is spelled out by the International Workshop on CLL. They have stood the test of time, they are very good. Patients over the age of 70, we don’t have a lot of satisfactory treatments so the more information we can get by putting them on to available clinical trials, the more we’ll learn about what the right decision in those patients happens to be.

But the clinician may well glean a lot of hope for the future, you’re saying.

I tell my patients that I think with the modalities that are there at the present time we’ll probably be significantly increasing the cure fraction in CLL in a period of 3-5 years.

Michael, thank you very much.

It’s been a pleasure.