EHA 2023 | Ponatinib & blinatumomab for Ph+ ALL

So, the historical standard of care for patients with Philadelphia chromosome-positive ALL has been intensive chemotherapy along with a tyrosine kinase inhibitor followed by stem cell transplant. We know that with later generation tyrosine kinase inhibitors, such as ponatinib, we have even higher rates of MRD negativity, and we’ve reported long-term survival of about 75% in patients when they received intensive chemotherapy with ponatinib. There’s also data looking at dasatinib and blinatumomab, so a chemotherapy-free regimen that looks encouraging.

And so, in this study we wanted to evaluate a chemotherapy-free regimen with blinatumomab but with ponatinib, which is a more potent TKI, in the frontline setting. So we’ve treated 60 patients so far. What we do is we give five cycles of blinatumomab in combination with ponatinib initially 30mg daily, and then we drop to 15mg once patients achieve a complete molecular response, so MRD negativity, and then patients receive at least five years of ponatinib single agent as a maintenance.

We see essentially everyone responds to this regimen. We actually get deep responses with a complete molecular response in around 87% of patients. And then now we’re using this next-generation sequencing MRD assay that’s sensitive down to 1×10^-6, so one out of a million cells, and we’ve seen 89% of patients achieve MRD negativity by this assay. We see very rapid rates of MRD clearance, for example, in the peripheral blood. We can see by two weeks into treatment with this chemotherapy-free regimen, we see that about half of patients have already cleared their BCR-ABL transcripts. And this is translated to very encouraging survival. So, we have an estimated two-year survival of 88%. We have seen some, a few relapses, some of the relapses have been in the central nervous system, and so that is a concern when we’re using chemotherapy free regimens. But importantly with this, we’ve only transplanted one out of the 60 patients. So we’ve seen is that this seems to be a chemotherapy-free regimen that also can overcome, potentially, the need for transplant in these patients. So, we’re very encouraged by the data. We wait for, of course, for longer-term follow-up. Because of the potential for CNS relapse, we do need to be cognizant of that since we’ve removed all of the chemotherapy. We do give 12 doses of intrathecal chemotherapy, but we’ve more recently amended the protocol to increase that to 15 and we hope that this will prevent the risk of CNS relapse for these patients.