In the treatment of ALL, especially adult ALL, we have made a lot of advances recently and it was mostly related to intensification of standard chemotherapy, taking some lessons from the paediatric advances obtained by increasingly using more intensive chemotherapy in these patients, the children actually. So that was the first big advance and the second one was for the Philadelphia chromosome positive ALL. At the beginning of the 2000s, early years, we used TKIs in these patients, first imatinib and then second then third generation TKIs. It contributed significantly to advances in this initially poor risk of adult ALL, very rare in children but very frequent in older adults. So these have been the two major advances.
Now we are experiencing a new era with new agents and essentially immunotherapy, whatever you call immunotherapy, it could be antibodies, simply antibodies like rituximab in CD20 positive patients. We published a study showing that the addition of rituximab in these 30-40% of patients who express the antigens, the CD20, significantly benefitted from the addition of rituximab. So that would be antibodies; that could be a new targeted treatment. I mentioned TKI in Ph positive but we have some other fields for investigation – using TKI in Ph-like which is a new subgroup of poor risk ALL frequent in adults. We can use also targeted treatment in early T-cell precursor ALL which frequently also harbours mutations of several types of tyrosine kinase. So that is interesting and we will do that certainly in the next year.
Most impressive results have been recently obtained by either antibody-drug conjugates – inotuzumab, ozogamicin, a compound with very impressive results in relapsed patients – and also with the BiTEs, the blinatumomab compound with similarly impressive results in relapsed and refractory patients. So the next field is to move all these drugs into front line treatment, maybe not only in high risk patients but first in high risk patients. But we can also make some advances in standard risk and eventually in good risk patients because survival of good risk patients is still around 80% so there is room for further advances.
Finally, progress in transplantation and CAR T-cell technology will certainly offer new options for more advances. I’m thinking about haplo transplant which has been discussed during this meeting which is a very interesting way to transplant the patients and obviously on CAR T-cell technology. So probably haplo transplant or, let’s say, transplantation in general and CAR T-cells will be restricted to high risk patients, firstly because of toxicities associated with these procedures. But there is a large panel of investigation now and maybe there will not be enough patients to do all these investigations together so we need collaboration and we need to not do exactly the same trial in one group as compared to another group in order to investigate all these different possibilities of new treatments in ALL patients.
How do you resolve the investment of resources in rare cancer types?
It’s raising very, very important issues and it will be very difficult to answer these issues because of the rarity of the patient subset. It has been done in Ph positive ALL because Ph positive is relatively frequent and because we had and we still have very effective drugs, TKIs, against BCR-ABL. What we observe in our group in France is that when you have a new targeted treatment like imatinib first in Ph positive patients we can revisit your backbone of chemotherapy and you can significantly reduce the intensity of chemotherapy. Eventually you can maybe reduce the use of stem cell transplantation in these patients. So, depending on the efficacy of your targeted treatment you can probably balance the use of new targeted treatments with the use of intensive chemotherapy to find a way to have a less toxic and more efficient combination. So this is an important consideration.
The other one is that it’s not because you are diagnosing a mutation in one individual patient, that targeted treatment will represent a benefit for one given patient. So it will be difficult to evaluate the real efficacy of new targeted treatments in a very, very small subset because of the lack of patients and the lack of a control group. We cannot imagine to do a randomised trial in a subgroup which represents only 1% of all ALL patients. So we have to think about new trials, new endpoints, new ways to prove that the targeted inhibitor is really effective, yes or no, because we are using this usually in combination with chemotherapy. So which is effective – the inhibitor or the chemotherapy? So it will be a real issue.
My fear is that everybody will use targeted treatment without evaluating targeted treatment because all these drugs will be relatively expensive. So we have to prove that it’s fairly a benefit. My fear is that personalised therapy will be also isolated therapies in one centre for one patient without communicating, without trying to evaluate really the result of these targeted, individualised treatments. But it will be very difficult.
I mentioned the difficulty to work on a subgroup of patients, for instance in AML, the midostaurin trial, midostaurin targeting a relatively frequent subgroup of AML patients, 30-40% of AML patients which represents a large subgroup of patients. It took twelve years to do the trial, the randomised trial, and to definitely prove that the addition of midostaurin is beneficial. We did rituximab, I mentioned a rituximab study in CD20 positive ALL. It took ten years to do the randomised trial, analyse the results and publish that it is the addition of rituximab is beneficial. So you see what I mean? And this is relatively frequent subgroups, how to do that if the subgroup is only 1%, as I mentioned.
The next years the work will be to introduce new treatments into frontline therapy because usually all new treatments are developed and registered for advanced patients or older patients in AML for instance, patients with relapsed, refractory disease. It’s not enough for us doctors, we have to use these efficient drugs to treat all the patients, not awaiting the relapse but preventing the relapse by using these agents. So this is what we have to do, this is academic work. This is our task to do that.
The second point, also important with respect to immunotherapies, is the use of these strategies in maintenance. ALL is one of the few diseases, there are other diseases but it’s one of the few acute diseases where maintenance treatment has been approved as beneficial. It was based on chemotherapy coming from the paediatric ALL work and results. Now we can revisit the maintenance phase of the treatment by using immune interventions like antibodies, blinatumomab and others.
