When I started it was a club of a few friends interested in CLL, now it’s a very “fashionable” disease for many reasons – biological, clinical, management and, I would say, also the fact that we’re living longer. So there are many more CLL patients around and the life expectancy is increasing so the landscape is changing dramatically.
How crucial is prognosis in CLL?
Prognosis is crucial. In the old days we knew that it was a heterogeneous condition, some patients with stable disease, some having very aggressive, but we didn’t really have a grip on this clinical heterogeneity. So the prognostic area has changed a lot because of biological markers. So if we want to we could expand on that but I think that is a key point. Now we have prognostic markers that can help us to define which patients have a likelihood of remaining stable or being slowly progressive or having a very aggressive disease.
Which are the markers that have emerged?
There are many markers, it has been a dramatically changing scenario with many markers having prognostic implications. If we want to be practical what we advise, and in fact we had a lunch debate on this topic, if it’s really important now, on which markers are important. The bottom line is that the really important markers are the 17p deletion and the p53 mutation. So if you have those markers and patients are progressing, these patients have, I would say, a very poor outcome. So these patients should be identified and treated accordingly.
Could there have been a long period of time where you were not aware these patients had a poor prognosis?
It’s a difficult point but even today you wouldn’t treat a patient only based on a biological marker, even today, June 2014. We would treat a patient if the patient has a need to be treated, so the disease is progressing. The point is that if a patient is progressing and has these poor prognostic markers then you’ve got to go for a more aggressive form of treatment including even a transplant. So that is a point, it’s not the marker itself that determines treatment, it’s disease progression and if you have the marker you have to treat in a different way or you should try to treat in a different way.
Can you talk about the difference that drugs such as Bruton’s tyrosine kinase appear to be making?
Yes, this is a major turning point, I would say, in the management, clinical management, of CLL. So far management of the disease has been mainly based on chemotherapy associated with an anti-CD20 monoclonal antibody, so chemo-immunotherapy. Bearing in mind, and this is very important, that most patients with CLL at the time of diagnosis are over the age of 70 so although 70 today is relatively young they are not kids and if you have to treat an over-70 you have to consider that the patients are less fit, they have comorbidities, so it is more complicated. So chemo-immunotherapy with the most utilised combination is relatively toxic. So if it’s OK in a young patient, in an over-70, 75, 80, it can be difficult or not doable, in fact. Now the new drugs you mentioned are extremely important because they are the first drugs that are, in fact, targeting a mechanism, they’re not chemotherapy. So they’re targeting a signal that goes to what we call the B-cell receptor which is important in maintaining the proliferation of the leukemic load. So we’re targeting the pathway through the receptor so it’s what we call a mechanism-driven form of treatment. It’s not exactly like imatinib for other or the tyrosine kinase for CML where you have a genetic defect; CLL does not have one defect but we are targeting the B-cell receptor. So these drugs are opening a new scenario because they can control the disease so it is a major change.
Do you have more information on the heterogeneity of CLL?
Now we have much more, as I mentioned, indication of these biological markers having a very important prognostic implication. So if we identify a patient who has a progressive disease and has, let’s say, a p53 disruption, whether it’s a 17p deletion or a p53 mutation, these patients need to be treated aggressively with the best possible treatment which today includes an allogeneic transplant if you can do it; if you’re 80, if you’re old, it could be obviously difficult but if you’re 50, 60, we would consider transplant in the algorithm of first treatment. The new drugs are opening a very interesting debate because there is a suggestion that these new drugs targeting the BTK or the B-cell receptor signal could be effective even in patients with these poor prognostic markers. I would say this is early days and we have to wait more and see in the long run if this is the case, I think it’s too early to say. Going into your specific question, is for instance there are drugs that are targeting the BCL-2. CLL has an over-expression of BCL-2 and now there are drugs that are anti-BCL-2 so that’s again targeting a mechanism. This seems to be another potential and very effective way of treating these patients. It’s still early days.
How do you choose your patients?
Again early days, we can’t choose yet. These drugs are not available yet. They’re starting to be available, some in the States, but it’s very early days. Now in Europe they’re at the European Medicine Agency but we don’t have them yet. We have clinical trials, so that is OK, we can put patients in clinical trials if they’re open but they’re not yet widely available.
If these agents become available would they apply to all patients with high risk CLL?
The indication if we take one of them, without making too many names, one is approved in the US but for second line treatment across the board. So it’s independent of prognostic markers. I guess the indication in Europe probably, we don’t know yet, could be the same, we’ll have to see. So we can’t say now. That would not be for first line treatment, that’s for sure, it would possibly be for second line treatment but we have to see the indication. It would be for any patient, irrespective of the biological markers.
When do you decide not to treat a patient with chronic lymphocytic leukaemia?
Now, we were mentioning earlier the heterogeneous clinical course of CLL. We tell our younger trainees or fellows that a considerable proportion of CLL patients should not be treated and considerable patients with CLL may never be treated. So you can live with CLL and die not of CLL but of other causes with CLL. So you can survive with a notable amount of leukemic cells. This is very relevant, particularly since most patients are elderly. So you can live with a disease like CLL and you can only treat when they progress, you shouldn’t treat earlier than progression. I started a few years back and the policy was exactly that – watch and wait, when the disease progressed you treated. Thirty years later it’s the same, we still do not treat prior to progression. When the disease progresses we should have some biological markers that should guide us on treatment, not to give treatment before but to guide us on the optimal treatment when we need to start.
The presence of a mutation would not indicate treatment?
Per se, today we say no, the patient has to progress. There are some patients with a p53 disruption who are not progressing so you have to wait. What is becoming important and relevant is that probably the percent of patients harbouring a p53 mutation is higher than we thought. So this should be, in an ideal world, we discussed it at the lunch debate, in an ideal world we would like every patient that goes to treatment to be tested and this is not happening because it’s cumbersome and the world is very big. We don’t all live in lucky countries where we can do it, so most patients are not tested worldwide.
How would you summarise the clinical guidelines for doctors at this moment?
As we say, summarising in general, a) you have to make a correct diagnosis. Even today, 2014, some patients come in and they are not accurately worked up. So first you have to be sure you’re talking about CLL and not of a closely related condition which should be managed differently. So you have to be talking of CLL. b) It depends on where you live and the resources you have. If you did prognostic markers and you have to optimise resources, which is a key point today, I think this should be done at the time when you are deciding you need to treat the patient. If you don’t need to treat you can wait. The problem will be that the patient may ask you because they go on the internet so they can see what they have read about these prognostic markers – will you do them? In theory it’s not necessary, we should do it at the time of progression. There it would be advisable to do at least a FISH for 17p and, if possible, sequencing for p53 because that should guide treatment. Then you treat a patient, if a patient relapses I think he should be again re-tested because at the time of relapse, the incident of p53 is dramatically higher so that’s very important. So that would be a flowchart I would think. I can’t go into treatment, it depends obviously on age, comorbidities, so that’s complicated to decide now. New drugs are coming on the scene but we’re not there yet. It’s a very exciting time and we’re going to see major changes, whether these drugs will be used alone or in combination, but we need more time.
What would be your take home message?
Yes, I think after many years it’s a very exciting time for CLL because we’ve learned a lot about the biology and now we’re starting to see new drugs. It’s not impossible that in a short time we will consider even a chemo-free approach for CLL, as we are doing for other leukaemias. So that could be a very important turning point.
