Our trial was looking at the role of the addition of blinatumomab to chemotherapy in patients who are MRD negative after induction chemotherapy. Blinatumomab is a bispecific T-cell engager molecule that has been approved by regulatory authorities in multiple countries for the treatment of patients with relapsed/refractory acute lymphoblastic leukaemia and also for patients with B-lineage acute lymphoblastic leukaemia who are measurable residual disease positive, or MRD positive, after treatment. In our study we wanted to see if the addition of blinatumomab to chemotherapy had a role in patients who become measurable residual disease negative after their induction chemotherapy.
What was the methodology used in the study?
We took patients between the ages of 30 and 70 who did not have the Philadelphia chromosome or the BCR/ABL gene rearrangement with B-lineage acute lymphoblastic leukaemia and we gave them 2.5 months of standard induction chemotherapy using a BFM-type regimen. If they achieved a morphologic remission with less than 5% blasts in their bone marrow then they could continue on study and they got one more round of chemotherapy, an intensification with high dose methotrexate and PEG-asparaginase to prevent the development of leukaemia in the central nervous system.
Following this they had a bone marrow biopsy and if they maintained their remission and were MRD negative by a standardised and centralised flow cytometry method for assessment of MRD, they were then randomised to receive four cycles of consolidation chemotherapy or to receive that same four cycles of consolidation chemotherapy plus four cycles of blinatumomab. Recall that blinatumomab is given by a continuous intravenous infusion for four weeks at a time and that consists of one cycle. So we gave two cycles of blinatumomab to those patients, then they got three cycles of consolidation chemotherapy like the other patients, then they got another cycle of blinatumomab, another cycle, a fourth cycle, of chemotherapy and then last a fourth cycle of blinatumomab and then they could go on and get maintenance therapy.
At the discretion of the treating physician, patients could be taken off of chemotherapy and go to an allogeneic transplant using any conditioning regimen or any donor. So that was the design of the study.
What were the key findings?
What we found was that we randomised 224 patients. Now, we had originally enrolled 488 patients at the beginning of the trial, 81% of those patients went into morphologic remission – a CR or CRi – and they could go on and got the intensification. We lost some patients in there because even though they achieved a remission some of them relapsed fairly quickly, some of them had to go off study because of toxicity. So we randomised these 224 MRD negative patients, 112 patients to chemotherapy alone and 112 patients to the blinatumomab plus chemotherapy.
What we found was that at 3.5 years of follow-up that 83% of the patients that got the blinatumomab plus chemotherapy were alive, versus 65% of the patients that got chemotherapy. This was a statistically significant difference, the p-value was 0.003. The reason the blinatumomab plus chemotherapy patients did better was there was both a lower relapse rate in these patients and also somewhat less non-relapse mortality, but the big factor was the decreased relapse rate. So the blinatumomab was helping keep these patients in remission and improving their survival.
How do you think these results can impact the future treatment of B-lineage ALL?
We think that given these results, the significant improvement that we saw in the overall survival when we added blinatumomab, we think that this should be a new standard of care for these patients. This trial was designed actually as a registration trial from the beginning and the company that makes blinatumomab are planning to submit our data to the regulatory authorities to get it approved for this new indication for the treatment of MRD negative patients.
At the time of the bone marrow biopsy after the intensification chemotherapy, there were 62 patients who were MRD positive. Now, we had originally intended to randomise these patients also and we did that in 44 patients so there were 22 MRD positive patients that went to chemotherapy, 22 that went to blinatumomab plus chemotherapy. But the study accrued patients between 2013 and 2019 and in the course of the study the Food and Drug Administration here in the United States approved blinatumomab for the treatment of MRD positive patients. So we felt that we could no longer randomise them and subsequent patients who were MRD positive were assigned to the arm of the study that got blinatumomab plus chemotherapy.
So we ended up having 40 patients who were MRD positive that got blinatumomab plus chemotherapy and 22 patients that were MRD positive that got chemotherapy. What we found also was, obviously, a better survival for the MRD positive patients who got blinatumomab plus chemotherapy. Because we had smaller numbers the p-value for this difference was not statistically significant, it was 0.066. But, as I mentioned, blinatumomab is already approved for the treatment of MRD positive patients so that would be considered their standard of care.