ASH 2025 | Ponatinib plus blinatumomab versus imatinib and chemotherapy in Ph+ ALL: the GIMEMA ALL2820 trial

This is the first worldwide randomized trial comparing a chemo-free approach versus chemotherapy plus imatinib for newly diagnosed patients with Philadelphia positive ALL. So the chemo-free approach was based on ponatinib at two different doses because there was no upper age limit, so for young patients who were starting with 45 milligrams, whereas for patients older than 65, we were using 30 milligrams to start, and after that, after the induction phase, patients were receiving at least two cycles of blinatumomab, IV blinatumomab, for a maximum of five cycles. As for the control arm, this was based on imatinib, which is the only approved TKI in Italy, plus chemotherapy. Two different regimens, again, according to age, and the primary point was to prove if a chemo-free strategy was better. In this trial, there were three other points that were quite important. The first one was that there was a crossover foreseen if patients in the control arm were still MRD positive. The second point was represented by the fact that for the first time we decided that transplant allocation was not left at the investigator’s choice but was based on biological features, particularly persistence of MRD, occurrence of a mutation, and the presence of the so-called IKZF1 plus genotype. The fourth point was represented by the fact that we tried to implement CNS prophylaxis, which was a problem in the previous D-ALBA study. Just briefly, what we showed was that if we look at the hematologic responses by the end of induction, those are highly more significant in the experimental arm, reaching 90% versus 79% in the control arm. The induction deaths were completely different in the two arms. It was 2% in the experimental arm and 10% in the control arm. Looking at molecular responses, what we saw was that in the experimental arm, by the end of induction, the molecular rates were 40%. And this was not statistically different compared to the control arm, which is somehow expected because we know that in the control arm they were receiving imatinib plus chemotherapy. At variance, if we look at the same difference after blinatumomab, there is a striking, highly significant difference because in the experimental arm the rate of molecular responses is 70.9% versus 48%, and these results also compare favorably to the previous D-ALBA trial. Relapses in general were very few in both arms. In the experimental arm, we experienced nine relapses, and in the control arm, we experienced six relapses, but I just forgot to mention that there was a two-to-one ratio, so it’s obvious that the relapses were more in the experimental arm, and three of them occurred in patients who had to stop because of toxicity. The most important finding is event-free survival and overall survival because the event-free survival is highly statistically significant in favor of the experimental arm, reaching 90% versus 77%. Overall survival took into account also crossover patients, which were overall 31, and what we could prove that with immediate median follow-up of 23.5 months, so almost two years, overall survival is 94 percent in the experimental arm, 97 percent in the patients who crossed over, and 77 percent in the patients who were treated according to chemo plus imatinib. And these findings for me are really relevant because it means that also the crossover strategy, so just starting a chemo-free approach in patients who are persistently MRD positive, can be of value to treat patients. Transplant rate was much lower than before because just 20% of patients were allografted according to the guidelines that were provided. So, in conclusion, this work really shows that a chemo-free targeted approach based on ponatinib, possibly plus immunotherapy, should be the way to treat patients with newly diagnosed Philadelphia positive ALL.

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