Consolidation Immunotherapy With Blinatumomab Improves Survival in B-ALL

Patrick Bwon, MD

Patrick Brown, MD

Both disease-free survival (DFS) and overall survival (OS) were improved with the use of blinatumomab (Blincyto) as consolidation therapy for patients with B-acute lymphoblastic leukemia (B-ALL) compared with standard chemotherapy in a phase III clinical trial presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

Blinatumomab demonstrated a tolerable toxicity profile as well, with lower toxicities compared with the chemotherapy control arm. Due to the benefits observed early on in this clinical trial, accrual was halted early as the results demonstrated the promise of a new standard of care for patients with B-ALL in their first relpase.

Prior to this study, blinatumomab, the immunotherapeutic agent, was available for multiply-relapsed patients with B-ALL. However, these data suggest moving immunotherapy earlier in the treatment landscape provides optimal outcomes for patients who are most likely to relapse again and require a bone marrow transplant.

In an interview withTargeted Oncology,Patrick Brown, MD, chair of NCCN Guidelines for Adult and Pediatric ALL, and director of the Pediatric Leukemia Program at Sidney Kimmel Comprehensive Cancer Center, discussed the results from the randomized phase III study evaluating blinatumomab in patients with B-ALL. He also highlighted next steps for this research in terms of how blinatumomab may play a role in other patient populations of B-ALL.

TARGETED ONCOLOGY: What was the rationale for this trial?

Brown:For children and young adults with first relapse of B-ALL, the cure rates have traditionally been lower than we would like, somewhere around the 40% to 45% range. That is with our current standard of care therapy, which is a month of reinduction chemotherapy to try and reduce the second remission, followed by 2 to 3 additional months of chemotherapy for consolidation. Finally, for those patients who can achieve a second remission, they would receive a bone marrow transplant. The rationale for the trial was to try to take some of the advances in immunotherapy in ALL and apply them to this patient population.

TARGETED ONCOLOGY: What is the role of blinatumomab in this space?

Brown:With blinatumomab, there had been a study in children specifically in the relapsed/refractory setting that led to FDA approval for both pediatric and adults in the multiply relapsed setting. More recently in adult studies, it had been studied in an MRD-positive setting as a bridge to transplant. It had shown enough effectiveness that the FDA granted it accelerated approval, conditional on confirmatory studies. Our study was 1 of those confirmatory studies for demonstrating efficacy of blinatumomab in the relapsed MRD-positive setting.

TARGETED ONCOLOGY: What was the design of the trial?

Brown:The trial was a prospective randomized trial. As I mentioned, all patients would get a first month of reinduction chemotherapy, and then at that point, [we looked at] the patients that met the criteria for having a high-risk relapse, which are the patients we know need a bone marrow transplant to give them the best chance of cure and those are patients with early relapses or with late relapses that are MRD-positive. Those patients, at the time of completion of the first month of therapy, were randomized to either receive 2 additional cycles of chemotherapy, which is the standard, or they were enrolled to the experimental arm, which was 2 cycles of blinatumomab. All patients went to transplant after that.

The primary end point was disease-free survival (DFS) from the time of transplant. We expected, based on our prior studies, that the control arm would be associated with a DFS of approximately 45%, and we were powered to improve that to about 63%, so an 18% increase in DFS.

TARGETED ONCOLOGY: What were the results?

Brown:The results showed that we did, in fact, meet that criteria of increasing DFS, so in fact, the experimental arm had a 19% increase in DFS at 2 years, and the overall survival had a greater increase for the experimental arm compared with the control arm.

This was determined at an earlier time point than we had anticipated. We saw this difference and thought it was time to stop randomization because we felt a new standard of care of therapy had been identified.

TARGETED ONCOLOGY: What are the implications of thesedata?

Brown:The main implication is that we have a new standard of care for patients that are children to the young adult age range with B-ALL. It is an exciting advance because it is moving immunotherapy from the multiply relapsed/refractory setting earlier in the disease course to where we can potentially use immunotherapy as a strategy to cure more patients before they get to the point where they are relapsed/refractory.

TARGETED ONCOLOGY: Could you discuss the toxicity profile of blinatumomab?

Brown:One of the major reasons that the outcomes were so much better in the blinatumomab arm was because it was so much better tolerated than the chemotherapy arm. For example, the rates of serious infections were strikingly higher in the control arm. Blinatumomab does have some unique toxicities, such as cytokine release syndrome (CRS) and neurotoxicity. Fortunately, in the patients that we treated, the rates of those toxicities and the severity were very low. The rate of CRS was only about 20%, and nearly all of those were grade 1/2 which is very easy to manage with supportive care. Similarly, rates of neurotoxicity were somewhere in the 10% to 15% range. Again, they were all relatively low-grade and were completely reversible.

Overall, the tolerability profile of blinatumomab was far superior to chemotherapy. I think that was 1 of the big reasons that the patients were able to make it to transplant for curative therapy.

TARGETED ONCOLOGY: Are there any immediate next steps planned?

Brown:This is an early look at the data. We ended up accruing 95% of the planned accrual since we had to stop accrual early due to the superiority. We will be following these patients for longer, though. Currently, our median follow-up is 1.4 years, which is fairly long along the timeline so we don’t anticipate major change. However, it will be important to follow the study results and continue to report longer-term outcomes.

The main implication of the data in terms of the next steps would be to test whether blinatumomab could also be effective in the low-risk relapse population. Those are patients who have relapses that can be cured often, so we are testing whether blinatumomab can improve the cure rates and have better tolerability in that setting.