Expert Discusses Success of Blinatumomab in ALL

Hagop Kantarjian, MD

The anti-CD19 agent blinatumomab (Blincyto) received an accelerated approval from the FDA in December 2014 as a treatment for patients with Philadelphia chromosome-negative (Ph-) relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The approval was contingent on results from the confirmatory phase III TOWER trial, which have now been published in The New England Journal of Medicine. Based on the TOWER data, Amgen, the manufacturer of blinatumomab, has submitted a supplemental biologics license application to the FDA for the full regulatory approval of the agent.

In the TOWER trial, the median overall survival with blinatumomab was 7.7 months versus 4 months with standard chemotherapy in patients with heavily pretreated Ph-relapsed/refractory B-cell precursor ALL. Moving forward, lead study author Hagop Kantarjian, MD, is pushing for blinatumomab to be moved into the frontline setting.

“I think now this the time for us to start looking at these monoclonal antibodies in combination with chemotherapy and then move them to the frontline setting. The long-range idea within 5 years would be to combine these monoclonal antibodies with chemotherapy in the frontline setting,” says Kantarjian.

OncLive: Please provide some background on your research.

In an interview with OncLive, Kantarjian, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the success of blinatumomab and next steps with the anti-CD19 agent.Kantarjian: In ALL, we can cure, at best, 40% to 50% of patients—and that requires intensive chemotherapy that lasts for about 3 years. It is intensive, it is toxic, it is long, and it is associated with long-term complications. The monoclonal antibody therapy is going to be a breakthrough for adult ALL. The first breakthrough was with rituximab (Rituxan), the CD20 monoclonal antibody—when we add it to chemotherapy, it improved all comers. So, this was something that we piloted in 2002, and it was confirmed in randomized studies by the French more recently, in 2012 and 2014.

Now, blinatumomab is a part of the new wave of targeted antibody therapies. ALL cells express not only CD20, but CD19 and CD22 as well. Blinatumomab is a bispecific monoclonal antibody construct that targets the CD3-positive T cell. It then gets close in proximity to the CD19 ALL cell—that is how it kills the leukemia.

The first studies were done in Germany, and they showed that blinatumomab, as a single agent, is active. Which lead to the current study where we compared it in the setting of relapsed/refractory ALL. We treated 405 patients who were randomized 2:1 to blinatumomab or standard chemotherapy, and the study confirmed that blinatumomab is superior to chemotherapy. It improves survival 7 months versus 4 months. Also, it improved the rates of remission and negative minimal residual disease (MRD).

Now, this is the first building block, because as a single-agent it does improve the outcome, but we can do much better. How can we do better? By combining blinatumomab with chemotherapy and then moving it into the frontline setting.

What are the next steps with blinatumomab?

Do you think that this means the standard of care will change in the next 5 to 10 years?

Another monoclonal antibody which is different—it is not specific; it is attached to a chemo-toxic—is called inotuzumab ozogamicin. We did a similar study with that, which was a randomized study of inotuzumab versus chemotherapy. It showed very similar data in terms of improving survival and improving response rates.The next steps are to move it to the frontline. We know if ALL patients have MRD in first remission, their outcome is bad. By giving them blinatumomab, we can render 80% of them MRD negative, and their survival is significantly better than the historical data. So, I think now we should move blinatumomab into the frontline setting with chemotherapy and in the salvage setting, we should combine it with chemotherapy, too.Very much so. I think what we are seeing is a slow-motion evolution in the treatment of adult ALL, like we saw with chronic myeloid leukemia (CML) in 2000 with the tyrosine kinase inhibitors, and like we are seeing in chronic lymphocytic leukemia with the B-cell receptor inhibitors and venetoclax (Venclexta). Also, it is much like what we are seeing in the solid tumors with immunology studies with checkpoint inhibitors.

What should community oncologists take away from these recent findings?

Monoclonal antibodies added to chemotherapy in the frontline setting and combinations of monoclonal antibodies in the frontline setting are going to drastically change the treatment and prognosis in adult ALL within the next 5 years.I would like community oncologists to realize that there are these new treatments with targeted monoclonal antibodies, that they are highly effective in ALL, and that we are moving forward with further studies that combine these monoclonal antibodies with chemotherapy.

So, if they have a patient with ALL who is newly diagnosed or in the salvage setting, they should consider sending them to centers that offer the combinations of monoclonal antibodies with chemotherapy.

The most pressing challenge in the field of ALL is to increase the cure rate and reduce the toxicity of the chemotherapy, and I think the monoclonal antibodies are going to help us to accomplish this. The faster that we can do the studies, the faster we can get the results and publicize them so that they benefit all adults with ALL.

Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783.