We examined the impact of treatment delays in patients who were treated on the ECOG E1910 clinical trial which was a large randomised phase III study that was intended to evaluate the impact or the effectiveness of using blinatumomab during front-line therapy for patients with Ph negative or BCR-ABL1 negative acute lymphoblastic leukaemia. Blinatumomab, for those who are not aware, was really the first bispecific T-cell engager. So basically it’s a CD3/CD19 bispecific T-cell engager that has a couple of approvals here in the US but mostly for patients who have measurable residual disease following induction in acute lymphoblastic leukaemia and also for patients who have relapsed disease following their initial therapy with acute lymphoblastic leukaemia. So the study question in the original ECOG E1910 study was to determine the role of blinatumomab in the up-front setting.

So, long story short, the study essentially showed that the addition of blinatumomab was associated with improved progression free survival and overall survival in blinatumomab-treated patients versus those who didn’t get blinatumomab treated patients. This was including patients who had measurable residual disease negative acute lymphoblastic leukaemia. So it really was a treatment paradigm shift.

In our particular study, which was a secondary analysis, we evaluated the impact of treatment delays between the start of consolidation and the beginning of maintenance therapy. The impetus for studying that was because, at least in the ALL world, we’re generally taught that we should avoid treatment delays wherever possible. In fact, a lot of people, I should say my colleagues who treat paediatric ALL, think that maybe some of the worst outcomes in adult acute lymphoblastic leukaemia patients is related to lengthy treatment delays whereas in the paediatric world treatment is really given in a very regimented fashion. So we sought to evaluate the impact of those delays and whether they impacted survival.

What was the study design?

There were 224 patients who were able to be randomised to consolidation with or without blinatumomab and, of those 224, 135 went on to receive maintenance therapy. So we looked at those 135 patients in the chemotherapy-treated arms and the blinatumomab-treated arms and we tried to determine if we divided patients into two groups, those who had no or short delay between the initiation of consolidation and maintenance and those who had a long delay. So the way that we defined those terms were looking at the median time between the randomisation to consolidation to the initiation of maintenance. If patients had started their treatment on or before the median they were considered to have a no or short delay and if they started their maintenance after the median duration they were considered to have a long delay.  We did some statistical analyses to determine if the duration of delay was associated with differences in overall survival or relapse free survival between the two groups, the blinatumomab and the chemotherapy treated groups.

What were the key findings?

Really, the surprising result that we found is that patients who had a long delay between initiation of consolidation and initiation of maintenance actually had improved overall survival. That was seen in both chemotherapy-treated patients and patients who had received blinatumomab. The patients who had no or short delay actually didn’t do as well in terms of overall survival. I will say that, at least based on our statistical modelling, the difference in survival between the two groups in the long delay did not reach statistical significance but was very close. But it was enough to really make us think about the fact that these longer delays actually do not negatively impact overall survival which was actually a very reassuring finding and supported the notion that it’s best to make sure that patients receive all of their cycles of consolidation chemotherapy rather than focussing too much on the timing of the treatment. So however long it takes to get through consolidation actually seems to benefit you.

The other interesting finding was that patients who were in the no or short delay group actually spent a longer time in the maintenance phase of treatment. So one would think that the longer amount of time spent in maintenance might potentially offset the difference that we were seeing in terms of survival between consolidation and maintenance. But it didn’t seem that spending more time receiving maintenance therapy actually achieved that.

I will say the relapse free survival benefit was restricted to chemotherapy patients and was not seen in the blinatumomab-treated patients as well.

What do you think is the clinical significance of these results?

This really challenges once of the central dogmas of ALL therapy, which is that patients must receive all of their treatment on time. So at least in the paediatric literature that is strongly supported but our findings suggest two things. As I mentioned earlier, one of the biggest findings is that it’s mostly important to make sure that patients receive all of the recommended cycles of consolidation therapy, no matter how long it takes to get them because that seems to result in an improved survival benefit.

It also raises important questions about the role of blinatumomab during consolidation therapy because the ECOG E1910 trial was the very first study that evaluated the role of blinatumomab during the up-front treatment of ALL and so it’s now well integrated into front-line therapy but it also calls into question whether or not receiving blinatumomab during consolidation may potentially make us rethink how much maintenance a patient needs to receive in order to complete their treatment.