EHA 2021 | 25-month follow-up on GIMEMA LAL2116: D-ALBA induction in ALL

Important to underline upfront that this protocol was for all adults, meaning that was for patients with 18 years of age upwards, with no up age limit. In fact, in the study there were very elderly patients that were recruited. This study was based on an extension of the philosophy that the GIMEMA cooperative study group in Italy has had for many years. It’s that of using an induction, only a TKI, so tyrosine kinase inhibitor, plus steroid and no systemic chemo. So, they started very many years ago. This was philosophy we adopted more than 15 years ago. In fact, the first paper we published in Blood and it was published, if I remember well, in 2007, so that’s 14 years ago. So, the study started earlier, so, it’s well over 15 years.

The idea came obviously from CML, where you control the patient with a TKI alone. So, we said, “Why don’t we consider doing this in the Philadelphia-positive ALL patients too?”. And we started with the elderly. So, the first study with imatinib was patients above the age of 60 with no up age limit, and in fact, the oldest patient was 89. And all patients responded, and all went into remission, which was very rewarding, particularly for the elderly because in the older days, for the elderly patients, we didn’t have anything to offer. Many got only palliative treatment because there was very little to offer. So, that was the start of a long story, and we went on over the years using second generation inhibitors, namely dasatinib, then we went to ponatinib. So, a number of studies and they’re more or less all published.

So this last study, which is the D-ALBA protocol, we added a third important step, which is the consolidation. So, it’s induction with dasatinib and steroids. But then the consolidation is, for all patients, irrespective of the response obtained with dasatinib, they all get immunotherapy with a monoclonal antibody, blinatumomab, bispecific. So, it’s a form of immunotherapy, because the antibody, as you know, targets the CD19, which is present on leukemic B-ALL cells. But the therapeutic effect is mediated by the CD3 component. So, it targets a second antigen, targets the CD3. So, it’s activating the host immune system of the patient itself, the CD3 cell. So, it’s a form of immunotherapy. So, it was induction and consolidation without any systemic chemo.

So, the two key points were, and have always been, that you have to identify the Philadelphia chromosome in all patients, rapidly in one week of still pre-phase. And the second is that you have to give a CNS prophylaxis. So, the only chemotherapy they get is in cerebral spinal fluid.

So, the data of the study were published in the New England journal last fall, and it was very rewarding. All patients went into remission, and we obtained the primary endpoint, which is after two cycles of blinatumomab, we obtain 60% of molecular responses, which increased after more cycles of being up to about 80%.

Now what’s happening at EHA is that Sabina Chiaretti has presented the update of our study, which is, I must say, rather rewarding because the data continue to look very promising in terms of responses and of molecular responses. And in fact, we have data that are projected that three years follow-up where the responses, which remained very good. And to give you the exact figures, because off by heart I never remember them, but at the projection at three years we have 80% overall survival and disease-free survival is 71%. So, this extremely good in patient. And I must say that half of the patients so far have only received a TKI. So, no chemotherapy and no transplant. Another proportion of patients have gone to transplant.

What has emerged again and confirmed to an extent what we observed, what we report in New England is the rate of molecular response that is well over 80% and continues to be so all the time. The other important point is MRD, key point, as we said we reported it in the publication, and it continues to be the case over time. Patients obtain a molecular response – those who are negative by quantitative PCR remain without events. Particularly if you don’t have additional genetic abnormalities at diagnosis. If they have ikaros plus genetic profile at diagnosis these patients do significantly less well. The update of the curve is 79% disease-free survival if you don’t have any genetic abnormality at diagnosis, 55% if it’s ikaros alone, and down to 41% if it’s ikaros plus. So, the genetic landscape at diagnosis is very important in order to actually define the prognosis of patients.

So, this is where we stand, and I think that’s a very important to underline. I should also, one final point is that the study was only stopped at the end of the consolidation. That was a primary endpoint. After that, the centers were free to treat patients as they wanted and were collecting all the data. And so far, half of the patient have been transplanted. And what is important is that transplant-related mortality is low and that is most likely because they haven’t had systemic chemotherapy. So, this I think is a very important point that leads us to probably change the strategy of the management of Philadelphia-positive ALL, at least in adult life.