When I started with Ph positive ALL about one and a half decades ago people thought I was crazy. It was a disease with an absolutely dismal outcome, close to a death sentence. But I was intrigued by some preclinical work that had been done with what is now known as imatinib and so from the preclinical work we then went into the clinic following the lead of the CML studies and we established that it was actually quite active. It turned out to be even more active in patients who had not failed prior treatment which is the typical approach. So that led to a lot of trials both in Germany, where I was at the time, and of many international study groups and major centres to look at the value of initially imatinib and then subsequently the second generation TKI, both alone and in combination with various types of chemotherapy. Although we still have a long way to go, it is now no longer the type of leukaemia that has the worst prognosis. We’ve had dramatic success and we have a number of ideas on the strategies of how to improve further.

Could you tell me how drugs like imatinib have changed the landscape for treating?

It has changed it dramatically because even with the first generation TKI 90-100% of the patients achieved a complete remission which was far in excess of what we’d seen before. In elderly patients it was more in the range of 50% and even in younger patients who received more intensive chemotherapy we achieved a complete remission maybe in 70%. So going from there to 90-100% was a dramatic change. The problem that we have with all of these TKIs if we use them alone or with chemotherapy is that the majority of patients relapse. So these remissions are not sustained and this necessitates a treatment strategy which starts with a TKI-based treatment but so far, and I’m still a firm believer in it, incorporates allogeneic stem cell transplant if at all possible.

So there are a few patients who actually have lived long term relapse free without a transplant. We’re not able to identify them a priori. There are some surrogate markers that have been developed, like minimal residual disease as the foremost marker, which do give us an indication of what patient will definitely need intensive transplant as post-remission therapy. But even patients who are MRD negative do not necessarily avoid recurrence. So that is where we are.

Traditionally age has been a poor prognostic factor in ALL in general and that also applies to Philadelphia positive ALL. Now the GRAAPH trial is actually a beautiful trial, I like it very much, it’s mature data, it’s a prospective, randomised trial which addresses a number of very important aspects starting from the role of the intensity of the chemotherapy, showing that actually less is more. So that with a TKI-based treatment you can actually reduce chemotherapy, possibly avoid most of it in the initial stages of treatment. So you have less treatment related mortality and far less morbidity which is of huge benefit for the patients. It further shows that overall allogeneic stem cell transplant has a clear survival advantage for the patient but it in addition has a number of unique findings, some of them which were unexpected. So, for example, there is a subset of patients who have a good molecular response who are able to have the same long-term outcome with autologous transplant than as compared to allogeneic transplant. Of course autologous is easier to deliver, it doesn’t have the post-transplant complications.

So this was one remarkable finding, another one was that patients who had a very good molecular response actually did well or equally well with chemotherapy and with allogeneic transplant. Now, the data between study groups differ and I would like to emphasise that the long-term outcome in these trials was in the range of about 50% which means we still have to improve a lot.

Chemotherapy is on our first list of agents that we would like to eliminate and that’s where immunotherapies come in. At different stages, starting from the onset of treatment, where we are planning a clinical trial within the EWALL, the European Working Group for Adult ALL where we actually want to combine as an exploratory arm a TKI with blinatumomab. Now hopefully this trial will be realised and that would actually be the first essentially chemo-free trial for Ph positive ALL. There’s a little bit as pre-phase when you have to establish the diagnosis and you have to have some intrathecal therapy to protect against central nervous system relapse but otherwise it would be a chemo-free approach and possibly also transplant free, that remains to be determined.

The other areas where immunotherapy can make an impact either in replacing components of the chemotherapy or as an intervention when a patient has a molecular failure, but not yet relapsed overtly, is during consolidation and maintenance cycles. Apart from blinatumomab, inotuzumab is an interesting drug, an anti-CD19 antibody conjugated with a cytotoxic agent. There are a number of other drugs in clinical development by various companies that target these surface structures on ALL cells and could have the potential to be additional game changers. All of them, as far as I would say, in combination with TKIs and there we also have an interesting addition to the armamentarium which is ponatinib, the only approved TKI at the moment that is active against a very problematic kinase domain mutation which is a cause, a major cause, of resistance in the majority of patients who relapse on dasatinib for example. If we use it up front and with me it’s been pioneered by colleagues at MD Anderson Cancer Center but also the GEMIMA, the Italian Study Group, has a trial actually with monotherapy that looks exceedingly promising.

Any last thoughts?

No, I think looking back we have achieved a lot, both diagnostically and therapeutically. We should, as the central message, always consider that if we have haematological relapse in this disease it is a very tough task and usually unsuccessful. So using molecular therapies guided by molecular diagnostics is the core of what we will continue to pursue and I’m very optimistic.