The study that we presented data from at ASH this year was AALL-1731. That was a phase III trial conducted by the Children’s Oncology Group that enrolled children with NCI standard risk B-cell ALL and by that we mean children who are between the ages of 1 and 10 at diagnosis and have a presenting white blood cell count of less than 50,000. B-ALL is the most common cancer in children and NCI standard risk is the most common subset of B-ALL so it’s a pretty large patient population.
Patients who were determined to be at average or higher risk of relapse in this trial were randomly assigned to receive our standard chemotherapy or that same chemotherapy plus two cycles of blinatumomab. Blinatumomab, as probably most are aware, is a bispecific T-cell engager so it binds to both the B lymphoblast and then to the patient’s own T-cells, engaging them to kill the malignant B cells.
What we found at our very first interim efficacy analysis when we’d reached 40% of expected events is that blinatumomab significantly improved disease free survival in the overall randomised cohort, which included about 720 patients per arm. We saw 3-year disease free survival of 96% for those patients randomised to receive blinatumomab compared to 87.9% for those randomised to receive chemotherapy alone. Those outcomes, we saw similar improvements in outcomes if we looked at just the intermediate risk group, if we looked at the high risk group, if we looked at patients who were MRD positive at the end of induction and MRD negative at the end of induction. All the usual poor prognostic factors, to an extent, were neutralised by the addition of blinatumomab to therapy.
The improvement in disease free survival was secondary to a significant reduction in bone marrow involving relapses. We saw significant reductions in the cumulative incidence of relapse in the overall cohort as well as in the individual arms of the study as well. Blinatumomab doesn’t have great CNS activity so we didn’t see a reduction in the more rare event of an isolated central nervous system relapse but that wasn’t surprising given blinatumomab’s known sites of activity.
Overall, blinatumomab was really well tolerated in the context of this trial. We saw low rates of blinatumomab’s known target toxicities of cytokine release syndrome and neurotoxicity including seizures and encephalopathy. We didn’t see any differences in the rates of infectious complications in our higher risk patients who received blinatumomab but in that intermediate risk group we did see increased rates of grade 3+ sepsis and catheter-related infections. Some of those infections occurred during blinatumomab cycles but most of the difference was really secondary to increased rates of those events occurring in the chemotherapy courses that followed completion of blinatumomab up to and beyond a year after the patient had completed all their blinatumomab therapy.
But overall our results clearly demonstrate that the addition of blinatumomab significantly improves disease free survival in NCI standard risk B-ALL at average or higher risk of relapse. It’s overall well tolerated and so, in sum, our results clearly indicate that blinatumomab added to standard chemotherapy should become a new standard treatment for most patients within the NCI standard risk B-ALL.
Is there anything else you would like to add?
No, just as always, I’m the one who gets to talk about this trial but it was the result of the efforts of literally thousands of people – the entire 1731 study committee, every site that opened this trial and figured out how to give a continuously infused medication 28 days at a a time, and all the, of course, families who considered enrolment in this trial, they’re the real heroes of the story.
Then the last point that I’ll make is that we know blinatumomab works for this disease but our impact isn’t as strong as it should be unless we can get it to every patient who would benefit from it. So it’s going to take advocacy from paediatric oncologists and the whole cancer community and partnerships with the pharmaceutical industry and governmental agencies to make sure that patients can access this drug, both in privileged countries and certainly in a more global community as well. So that’s something that should be a great focus of the community moving forward.
