ASH 2024 | Blinatumomab and ponatinib for newly diagnosed Ph+ ALL: updated results and predictors of relapse

So the standard of care for patients with newly diagnosed Philadelphia chromosome positive ALL for many years has been chemotherapy with a BCR-ABL tyrosine kinase inhibitor and then transplant in first remission. Recently there’s been emerging data with the use of more potent TKIs such as ponatinib as well as chemotherapy-free regimens such as the regimen from the D-ALBA study of dasatinib and blinatumomab. We’ve also reported some of our early data with ponatinib and blinatumomab, a chemotherapy-free regimen for patients with newly diagnosed Ph-positive ALL, and reported very encouraging early data. So this particular abstract, we’re reporting longer-term data for these patients, and really we’re focusing on looking at the predictors of relapse in this population. We did genomic sequencing, and we’re trying to determine what are the predictors of relapse for patients treated with this chemotherapy-free regimen. So we enrolled patients with newly diagnosed Philadelphia chromosome-positive ALL. We treat them with five cycles of blinatumomab in combination with ponatinib. Ponatinib is initially started at 30 milligrams daily and then reduced to 15 milligrams daily once patients achieve MRD negativity. And then we give patients at least five years of ponatinib maintenance. So in this abstract, we’re reporting now 76 patients treated with this regimen in the frontline setting. We continue to report very good response data, essentially, aside from one early death, all patients have responded. And importantly, we see very deep levels of response. So with an NGS-based MRD assay with a sensitivity of 10-6, 98% of patients achieve MRD negativity. So now we’re presenting updated survival data. So the three-year overall survival with this regimen is 88%. And importantly, with this chemotherapy-free regimen, we’ve only transplanted 2 of the 76 patients. So essentially, this is a chemotherapy-free and also transplant-sparing regimen. Now, that said, we still do see some relapses. So we had 10 relapses out of the 76 patients. We tried to characterize these relapses and tried to determine what are the predictors. So we did genomic sequencing, and we looked, for example, for the IKZF1plus gene signature, which other groups have reported as prognostic in Philadelphia chromosome-positive ALL. So looking at all of the potential variables, we actually identified three on univariate analysis that were predictive for relapse. That was elevated white count at a level of over 70,000 at diagnosis, the presence of a VPREB1 deletion, which is sort of a novel finding that others haven’t reported, as well as the presence of CNS disease at the time of diagnosis. Interestingly, we did not find IKZF1plus gene signature to be associated with an increased risk of relapse. We look at multivariate analysis. The only factor that was predictive for relapse was the high white count over 70,000. So these are patients that we now consider as high risk for relapse with this regimen. In fact, these patients had a cumulative incidence of relapse of almost 50%. So we’re now investigating other strategies for this high-risk population and considering novel strategies such as potentially CAR-T cell consolidation. And we’re still trying to avoid transplant for these patients, but we do need more strategies to reduce the risk of relapse.

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