Ph-positive ALL has improved dramatically over the years. It used to be the worst prognosis type of ALL and with the advent of the tyrosine kinase inhibitors that has improved but there are still quite a number of unanswered questions and certainly a way to improve treatment. One of the initial core questions in approaching the patient is which kinase inhibitor should you use and, secondly, which type and which intensity of chemotherapy is needed.
A lot of the data available are still with the first generation kinase inhibitor imatinib. More recent trials have focussed on the second and third generation kinase inhibitors which are more potent and they hold considerable promise but in all honesty the field has suffered from the fact that they’ve never really done a formal head-to-head comparison of these. So we have to extrapolate from smaller trials and definite proof that the more modern kinase inhibitors are really better is not there yet, although there are a lot of suggestions that especially the third generation kinase inhibitor, ponatinib, might actually be having more than an incremental change.
The second question, which I think has been more clearly answered, is how much chemotherapy do you need. There we have learned that reducing the intensity and therefore the toxicity of the chemotherapy is actually beneficial. There is reduced morbidity and reduced mortality without negatively affecting the long-term outcome of the patients.
One of the central issues of the field, and it’s increasingly contentiously discussed, is whether or not you need a stem cell transplant and, more specifically, allogeneic stem cell transplant. In general if you look at the whole population there still is consensus that transplant is the most effective form of anti-leukemic therapy in Ph-positive ALL. It suffers from the still relatively high rate of non-relapse mortality which pulls down the survival curves. So the development has been going towards trying to define the patient populations that would have a greater probability of benefitting from transplant, especially by using minimal residual disease analysis.
So this has been implemented as a routine measure throughout treatment with MRD negativity or very low levels clearly being beneficial to the patients. The MRD level prior to transplant also seems to be informative and it is clear that the lower the level is, with or without transplant, the better the patient is likely to do. So two aspects: some groups actually now look exclusively at MRD as a risk factor and then transplant based on those results, others still routinely transplant irrespective of the MRD but everyone measures it.
Another interesting aspect relating to the MRD is that we are now not only using the BCR-ABL transcript but also the IgTCR rearrangement analysis that is more commonly done in the other types of acute lymphoblastic leukaemia and there are some discrepancies in a subset of patients indicating different biology. So this is a field of very interesting exploration.
Lastly, I addressed the post-transplant management; although transplant is the most effective form of treatment, patients do relapse thereafter. There are a number of trials of which only one is actually a prospective randomised trial but overall the data clearly suggests that the use of kinase inhibitors after transplant, either in a prophylactic manner or triggered by minimal residual disease signals, are clearly beneficial in terms of overall survival. So what is now happening is that trials integrate initially low intensity chemotherapy, probably still more intensive during the consolidation cycles, secondly, the more modern second and third generation kinase inhibitors and combinations with immunotherapy. That is where blinatumomab as a T-cell engaging bispecific antibody has attracted particular attention. It’s the only drug that actually is even approved for MRD positive disease, although in the Ph-negative field, so in the Ph-positive we are engaged, and several groups are engaged, in clinical prospective trials combining blinatumomab with kinase inhibitors. The hope is that actually we will be able to have a paradigm shift in which we are able to avoid chemotherapy almost altogether with the exception of prophylactic intrathecal therapy to avoid a CNS relapse.