Use of novel agents in childhood ALL

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Published: 6 May 2016
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Prof Lia Gore - Children's Hospital Colarado, Aurora, USA

Prof Lia Gore speaks with ecancertv at BSH 2016 about current and emerging treatments for all.

With a childhood cure rate of 95%, Dr Gore explores how treatments of ALL might have significant impacts in a patients later life, and how to reduce undue risk where possible.

The novel agents being trialled so far include courses of immunotherapy; monoclonal antibodies and CAR-T cells, and targeted therapies.

Prof Gore also addresses toxicities associated with treatment, and the challenges in treating the unregulated cell growth of cancer in a patient who is still growing.

 

ISH 2016

Use of novel agents in childhood ALL

Prof Lia Gore - Children's Hospital Colorado, Aurora, USA


I spoke about the use of new drugs and new agents in the treatment of childhood acute lymphoblastic leukaemia and it’s a very broad topic so it was a big challenge to try to think about how to summarise, in a sense, the really exciting progress that we’ve made in the last five years in particular.

What are the current standard treatments for ALL?

ALL is really the success story of oncology and paediatric ALL has had dramatic responses in the last thirty years. It went from being really a nearly fatal, universally fatal, illness to one where more than 95% of kids can be cured today. The challenge for ALL is several-fold. One is that we have tremendous success but sometimes at a significant cost for children in terms of long-term side effects. The first part of that is that when you have an adult with cancer and they survive twenty years past their cancer if they’re 70 when they’re diagnosed that’s pretty spectacular. But if they’re five when a child is diagnosed just twenty years later is really at the prime of their life. So as paediatric oncologists I think we’re very focussed on the very long term outcomes for these children and that’s a big challenge because we don’t know what the side effects of many of these chemotherapy regimens that we use might be forty and fifty and sixty years later.

So that’s the first thing. The second thing is that most of our regimens today have been designed and settled on because of lots of cooperation across oceans, among many institutions and many investigators with thousands and thousands of patients treated on clinical trials. We’ve settled on a combination chemotherapy regimen, we’ve been able to eliminate radiation from most children with leukaemia, and most of this therapy is fairly well tolerated but, again, side effects are significant and not always at a minimal cost for the children and their families. So the second challenge is to consider how can we do clinical trials that actually might allow us to reduce the burden of therapy for children who might be cured with less significant intensity of their treatment. So if we can do that that’s fantastic because we can really tailor the intensity and the aggressiveness of the treatment to the children who need it the most and we can spare other children a lot of significant side effects and long-term consequences.

The third thing is that there’s a subset of patients that we still have very poor outcomes from and those are patients with certain genetic abnormalities in their leukaemia that we’re able to detect at diagnosis but we’re just learning how to manage them or we don’t have adequate ways of managing them. The subset to that is that they’re patients who relapse; even though we think they’re going to do fine when they’re diagnosed and we think that they have a good outcome, there are some patients that we still can’t predict who is going to relapse and we don’t know entirely who those patients are who might benefit from either a completely different treatment approach or more intensive therapy than we already have. So our challenge, really, is to really risk stratify and to try to give therapies that are appropriate to that exact patient and that exact patient’s leukemic abnormalities.  Once we’re able to do that then hopefully we can raise the cure rate for everybody and decrease the toxicity burden for the vast majority of children who don’t need to have that toxicity.

So my talk really focussed on some of the new strategies that are really trying to focus and develop better treatment options for kids, first for the kids who have relapsed or who have very refractory disease for whom the current treatments are not adequate.

What novel agents have you been using?

There are a couple of categories, really, to break those down into. The first is immunotherapy and that would include things like monoclonal antibodies or chimeric antigen receptor T-cells. Monoclonal antibodies are kind of a broad category because there are a number of different types of antibody treatments. The most common are antibodies that are linked to a specific abnormality on the surface of the leukaemia cell and sometimes they contain a toxin that’s attached to them so it’s delivering a toxic payload to the leukemic cell. Some of them are actually newer forms of antibodies which engage the human immune system of the patient him or herself to better combat the leukemic cell and those are called bispecific antibodies or trispecific antibodies. Then there’s a whole class of treatments called chimeric antigen receptor T-cells which are engineered T-cells. They’re the patient’s own T-cells, part of their immune system, that actually can be engineered to be activated against the leukemic antigen on the surface of the leukaemia cell. That’s a very novel approach that has really come into its own over the last three to four to five years. The longest patients out who have received CAR T-cells are about three years out now. So that’s the main category of the immune-based therapies, there are other immune-based therapies that are in development but they’re just a bit younger and so they’re not quite as highly advanced in terms of progression into more widespread use.

Then there’s a whole series of what we’d call small molecule inhibitors or targeted therapies which are designed to attack either a protein or an enzyme or something that’s unique, a unique mutation in a cancer cell, for instance, that might not be present on the normal counterpart of the cell in the human blood system. Those are really a widespread variety, there are hundreds of them, literally, in development and we do know that there are certain recurring abnormalities in paediatric leukaemias for which some of these targeted therapies can be very effective when introduced appropriately. One of our challenges is to figure out how to introduce those therapies either concurrent with or in some sort of sequence with either immunotherapy or with other more conventional chemotherapy regimens because we know that conventional chemotherapy works for most kids and one of the questions is whether or not the new treatments can really synergise with currently available therapies or can be substituted for some of the more toxic currently available therapies and increase the impact of the treatment, decrease the negative impact.

How do you decide what treatments are introduced into clinical practice?

That’s the million dollar question. We’ve actually joked that as we get smarter about subsetting the types of molecular abnormalities in childhood leukaemia there are almost more drugs than there are patients because we do do quite well with the majority of kids with ALL. As we do genomic sequencing, as we learn more about the molecular abnormalities at the very cellular level of an individual patient’s leukaemia, we’re likely going to be able to identify really some personalised treatment options. That gets at the heart of your question, though, which is very complicated which is how do we assess whether or not they actually work. Many of these therapies are fairly expensive and we want to be able to prove efficacy and safety for them and the best way we can do that is to do really good clinical trials. Many of those trials have to be international in nature because of the very small numbers of patients who might be eligible for any one treatment and if that’s the case then you have to stretch your trial boundaries across many international borders to be able to collect enough patients in an appropriately timed way so that you have current data that you can really assess them in a thoughtful way and hopefully act on the data. Hopefully you can also build in to these trials in a variety of ways some companion biology studies so that you are able to figure out if the thing that you think you’re inhibiting is actually inhibited, if the target you’re actually trying to attack is actually attacked. Then you can really follow those patients hopefully much longer term to be able to determine whether or not that therapy is just a transient benefit or if it actually has a longer term benefit.

What are the issues of the toxicities of the drugs used in paediatric patients?

One of the things that we really, as paediatricians, we have to be cognisant of is that our patients are these growing, developing individuals; they start out a 3kg baby and grows into an 85kg gigantic halting adult. And being able to figure out what happens to normal growth along that way is really critical because many of the pathways that are abnormal in cancer are developmental pathways. They’re responsible for growth, they’re responsible for development and really cancer is uncontrolled growth. I think any parent that’s had a teenager feels that they have uncontrolled growth too as they’re replacing their shoes constantly and their kids are growing out of their clothes in front of their eyes. There are remarkable similarities between a rapidly growing teenager and a cancer cell that’s rapidly growing in that we don’t know in cancer cells how to shut them off sometimes, we don’t know how to make the cancer cells stop growing under certain circumstances.  So if we inhibit the pathways that are making that cell grow, which for a cancer cell is very important, what else are we shutting down? If we think about skeletal maturation, for instance, or development of the endocrine system, if we think about neurocognitive development, we might be shutting down something that’s critical to cancer but something that’s also very critical to normal neurologic development for instance. So being able to track those children over the long-term, being able to follow their growth carefully, being able to follow their pubertal development, for instance, watching how their cardiac function matures, all of those things are critical to be able to determine whether or not the therapy actually is going to have negative long-term impacts. And unfortunately those studies take a long time, you can’t rush development.

What is your take-home message?

The balance, the thing that’s trickiest for us and our biggest challenge, really, is to test the right agents in the right patients at the right time and to make sure that we do that in a collaborative way across borders so that we can really understand what is happening with the treatment – is it really what we think it is, and to share that information so that we can advance the field further. I’m always biased that even if a study doesn’t turn out to be what you hope the results are, even if you don’t cure as many children as you’d like to, hopefully you can learn something from that study that will be able to pass on to the next study and the next patients. I think it’s really incumbent upon us as investigators that if a patient is willing to participate in a clinical trial for us we want to be able to tell that child and that family that their participation really meant something, that it contributed to advancing the field. So it means that we have to make our trials smart, we have to construct trials that actually contribute to the field and answer questions. Even if the ultimate outcome is not that that drug is the right solution hopefully we’ve learned something along the way that allow us to introduce the next treatment regimen, the next therapy, so that we have advanced things and that we can narrow down the scope of what we’re doing so that we can actually have a positive impact on the next children.