Chemo-Free Regimen for Ph+ ALL Yields High Rate of Deep MRD Negativity

Updated results of a phase II study presented at the American Society of Hematology annual meeting showed that a chemotherapy-free combination for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) led to high rates of deep minimal residual disease (MRD) negativity and durable remissions without need for stem cell transplant in most patients.

In this exclusive MedPage Today video, Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center in Houston, discusses the results with ponatinib (Iclusig) and blinatumomab (Blincyto) in Ph+ ALL, including relapse predictors and next steps for high-risk patients.

Following is a transcript of his remarks:

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 (Sprycel) 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+ 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 mg daily and then reduced to 15 mg daily once patients achieve MRD negativity. And then we give patients at least 5 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 [next-generation sequencing]-based MRD assay with a sensitivity of 1 × 10^-6, 98% of patients achieve MRD negativity.

So now we’re presenting updated survival data. So the 3-year overall survival with this regimen is 88%. And importantly with this chemotherapy-free regimen, we’ve only transplanted two 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 [13%] 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 as on univariate analysis that were predictive for relapse. That was elevated white [blood cell] 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 [central nervous system] disease at the time of diagnosis. Interestingly, we did not find IKZF1plus gene signature to be associated with an increased risk of relapse.

We looked 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.