EBMT 2024 | Are transplantation and chemotherapy still necessary for all patients with Ph+ ALL?

This is a, I mean, it’s a very timely question nowadays, whether you really need a transplant in Philadelphia-positive ALL, which was absolutely essential in the past. The issue is that we have to keep in mind that many patients are elderly. In fact, one out of two more or less of the less young population, let’s say over the age of 50, 55 are Philadelphia positive. And transplant was the only way of saving these patients in the past, so it makes it more difficult. Now with the TKI, this has certainly changed and we’re questioning whether we still need a transplant. Now, why are we doing that? TKIs have impacted dramatically, and in my talk I gave the data with a different TKIs. And in addition to that, there’s been an added chapter of immunotherapy.

So in our last published study, the so-called D-ALBA study, which was for frontline patients with Philadelphia-positive ALL, all adults 18 years up with no upper age limit, all these patients received the TKI dasatinib plus steroids. And then they were consolidated with blinatumomab, this bispecific monoclonal antibody that is a form of immunotherapy that targeted leukemia B-cells. But it activates the host immune system targeting the T-cells of the patient. Now the paper first paper was published in the New England Journal of Medicine in October 2020, and the follow-up was published online last December in the Journal Clinical Oncology. And this was important because they showed the follow-up, long-term follow-up of these patients, and follow-up is 53 months, so that’s over four years. And the good point is that we had the survival curves that ranged between 75 and 80% at over four years, which is obviously very good news. And I said this morning at my talk that half of these patients did not receive systemic chemotherapy, nor transplant. And they’re doing well at more than four years follow-up. And why are they doing well? Probably because these have been very closely monitored for MRD by molecular testing, all centrally done at our center in Rome by quantitaive PCR. And almost all patients were MRD negative, sustained MRD negative, were not transplanted. And these patients have been doing fine and 96% are still in remission without having never received systemic chemo transplant. Patients with transplant were largely MRD positive. So MRD becomes a discriminant between transplant transplant.

Now I gave more data and I said at the end of the day that the study that’s ongoing now in Italy, the GIMEMA, which is the first randomized study, Phase III ever done for Philadelphia-positive ALL, we are randomizing ponatinib plus blina versus imatinib and chemotherapy. The [inaudible] is doing very well, we hope to finish enrollment overall 236 patients by the end of this year, beginning of next year. That study would be tailored exactly to define how many patients can be spared chemo and transplant. The data we have now indicate that this is possible in a proportion of patients, but nobody knows how many these are because no studies have been tailored to respond to this question. So this way, that’s why we believe that a good proportion of patients will be managed only with the TKI plus immunotherapy, without having to give systemic chemo and transplant.

Yeah, this I already alluded to. This was the recently published paper indicating long-term overall disease-free and event-free survival. So what I can add is that this was very rewarding obviously, because many studies you see the power of the first report, the early findings are very positive. Then follow-up becomes longer, results get, let’s say less exciting. These have held over four plus years, so this is very good news. What I can add is that one issue that we’d already noted in the first report is the issue of the CNS localization, of the central nervous system. We have reported that we were seeing patients in the last in a follow-up study. We’ve seen so far, only nine relapses, but 4 or 5, because one was partial, had the CNS localization. So that is something we have to be very careful at. I don’t think it’s more than in the past. It’s probably that we’re seeing less hematological relapse so this stands out. So based on these findings in the current study I mentioned earlier, the one that randomizing in the experimental arm ponatinib and blina, we’ve increased the CNS prophylaxis, increased to more intrathecal and with a triple combination of drugs. So far we haven’t seen any CNS localization but early days. So that’s where we stand. And again, the end of this study should give us further information also on the issue of CNS localization.