Hyper-CVAD and sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell ALL

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Published: 7 Dec 2020
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Dr Nicholas Short - MD Anderson Cancer Center, Houston, USA

Dr Nicholas Short speaks to ecancer about a study he presented at the virtual ASH 2020 meeting on the use of hyper-CVAD and sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell ALL.

He reports that all patients in the study achieved a complete response and 97% of patients achieved MRD negativity.

Dr Short hopes that these kind of regimens can lead to a transplant-free minimal chemotherapy regimen in the front line setting.

Read more about the study here.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

 

This study was designed to evaluate blinatumomab in the frontline setting in combination with intensive chemotherapy with the hyper-CVAD backbone. We know from other studies that blinatumomab is very effective in the setting of relapsed refractory B-cell ALL and also importantly to eradicate MRD for patients who have persistent MRD after initial chemotherapy.

The idea was that if we incorporate blinatumomab in the frontline setting across the board that we would deepen responses which should hopefully lead to decreased rates of relapse and ultimately higher cure rates but also that if we incorporate a very effective regimen in the frontline setting that we could potentially decrease the amount of chemotherapy that we have to deliver. So what we’re trying to do in the study is to shorten, actually, the duration of chemotherapy, the total intensity of the chemotherapy patients receive so that hopefully this will also in addition to improving long-term outcomes will also decrease potential treatment-related morbidity and mortality that can be associated with intensive chemotherapy regimens.

Could you explain the methods and endpoints investigated in this study?

This is a phase II study, the primary endpoint is relapse free survival although of course we look at response rates and other survival outcomes. Eligible patients have newly diagnosed Philadelphia chromosome negative B-cell ALL. The inclusion is relatively broad, the only thing that we particularly exclude is patients with significant central nervous system disease because of the potential interaction of blinatumomab and its potential role or ability to cause neurotoxicity.

The study design itself is we give four cycles of hyper-CVAD followed by four cycles of blinatumomab consolidation and then a maintenance which is actually a truncated version of POMP. So typically POMP maintenance is given for three years so what we’ve done is we’ve cut that about in half and then we intersperse blinatumomab into the maintenance phase. So we give three cycles of POMP followed by one cycle of blinatumomab and we alternate that.

In total the hyper-CVAD portion is cut in half, so from eight cycles to four cycles, and then the total maintenance phase is cut in half as well from about three years to a year and a half.

What were the key results?

Overall all patients achieved a complete response. Importantly, we looked at MRD negativity because we know that this is associated with better long-term outcomes for patients with ALL. All but one patient, so 97%, of the treated patients and we’ve treated 38 patients to date, so 97% of patients achieved MRD negativity, most of those before blinatumomab but there were three patients who were MRD positive prior to the initiation of blinatumomab and all of those achieved MRD negativity.

As I mentioned, the primary endpoint was the relapse free survival. Among the 38 patients treated so far there have been seven relapses and two deaths in remission. Notably, all of the relapses were in patients who had some baseline high risk feature. So in total the two-year relapse free survival is 71% and the two year overall survival is 80%. We think that this looks like it compares very favourably to historical outcomes. We’ve looked at this in comparison with a regimen that we did of hyper-CVAD and ofatumumab, so an anti-CD20 antibody without the blinatumomab, and the two-year overall survivals are the same but we’re beginning to see a plateau of the curve. So if that persists then it looks like the long-term outcomes of this may be superior to typical hyper-CVAD regimens without blinatumomab.

What is the future impact of these results in the treatment of refractory Philadelphia chromosome positive ALL?

We know that treating any acute leukaemia and in particular ALL that it’s important to give the most effective regimen in the frontline setting. Because we know that once a patient has relapsed, even if we have very effective agents at that point, the likelihood of achieving a long-term cure is relatively low. So this certainly shows the feasibility of this approach, of incorporating these effective regimens, in particular blinatumomab, into the frontline setting. Our goal really is can we cure patients in the frontline and not wait and save these drugs for potentially the relapsed refractory setting.

This is where the field is moving and there are a lot of other studies evaluating similar concepts of integrating either inotuzumab ozogamicin or blinatumomab in the frontline setting. So what we’re doing now is actually the study has now been amended and so what we’re going to be doing is incorporating inotuzumab ozogamicin in addition to blinatumomab into the frontline setting. Then the goal will be a total therapy in the frontline setting for patients with ALL aiming for as high cure rates as possible and hopefully also without a need for transplant for any of these patients. So a transplant-free, minimal chemotherapy regimen that incorporates these highly active novel agents into the frontline setting.

We’re particularly encouraged by the high MRD negativity rate. Then looking at the patients who have relapsed, all of those did have high risk baseline features. So in this particular study a third of patients had a high risk genomic abnormality, so poor risk cytogenetics or others. So those are the patients that we still… some of them certainly did relapse, but for patients without a baseline high risk abnormality we’ve seen no relapses to date, so that’s very encouraging.