Blinatumomab Potentially Poised to be Next Standard of Care in Acute Lymphoblastic Leukemia, Says Expert

Max Topp, MD

Max Topp, MD

Blinatumomab (Blincyto) almost doubles the overall survival of patients with relapsed/refractory acute lymphoblastic leukemia (ALL), according to Max Topp, MD.

In an interview withTargeted Oncology, Topp, MD, University Hospital of Wuerzburg, Internal Medicine, discusses the phase II TOWER study, the findings of which showed that blinatumomab improves the overall survival of patients with relapsed/refractory ALL from 4 months to 7.7 months. Topp also discusses the future of blinatumomab as a possible frontline therapy for these patients, and as a potential next standard of care for the disease type.

TARGETED ONCOLOGY:Can you give an overview of the TOWER study?

Topp:

The purpose of the study was to address the question of whether blinatumomab as a single agent immune therapy can render patients with ALL to survive better than patients treated with chemotherapy. Historically, chemotherapy in this patient cohort usually has an overall survival of about 4 months. Blinatumomab has been shown in a phase II trial, as a single agent, to lead to an overall survival benefit in a single arm study of 6.1 months. Thus, the aim of this study was to do a head-to-head comparison, and it was a 2:1 randomization where patients would receive standard chemotherapy.

The key finding of the study is that blinatumomab almost doubled the overall survival of patients with relapsed/refractory ALL from 4 months to 7.7 months.

TARGETED ONCOLOGY:What is the impact of those findings?

Topp:

With this randomized phase III trial, with a time-sensitive endpoint of overall survival, blinatumomab has established itself as the therapy of choice in patients with relapsed/refractory ALL. I think it is important to note that this drug can be given most of the time in the ambulatory situation, so it's very attractive to a patient who is relapsing after standard chemotherapy.

The second key point is that, looking at the safety of this drug, and talking about grade 3 or grade 4 safety events, usually the top lists are neutropenia and infections from complications, but blinatumomab definitely had a lower rate of these two components when compared to chemotherapy. On the other hand, blinatumomab has been associated with resulting in neurotoxicity. In the phase II trial, 14% of the patients actually had grade 3 or grade 4 neuropathy, which is always reversible within the first 48 hours.

In this trial, one key finding showed that the rate of neurotoxicity was reduced to 8%, and secondly, that the patients who received standard chemotherapy also had 9% neurotoxicity. It was a surprising result to see that the neuro events were common in patients treated with standard chemotherapy. On the other hand, immunotherapy, specifically using T-cells as the payload to get rid of leukemia, reduces cytokine release syndrome.

In this trial, the rate of severe grade 3 and grade 4 cytokine release syndrome was less than 5%, and none of these patients had to be treated in the ICU. This is actually really well-controlled by just giving the patient steroids, which doesn't block the effect of the immunotherapy, and no patient has had to go to the ICU in that context. It's usually within the first week of therapy, so those findings are very significant. This drug has a visible safety profile, and maybe even better than standard chemotherapy in this setting.

TARGETED ONCOLOGY:Can you talk a little bit about the mechanism of action?

Topp:

Blinatumomab is a fusion protein of two antibody derivatives. After cloning out the VL and VH regions of the respective antibodies, they are fused to create a very small molecule that has a very short half-life. When given to the patient, blinatumomab will first bind to the leukemia cell by interacting with CD90 before attracting the T-cell. The T-cell will then be brought within such a close proximity that it can exert the kiss of death to the leukemia cells. The T-cells will then go on and seek out another leukemia cell and kill that off. Essentially, the T-cells engage in serial killings of these leukemia cells.

TARGETED ONCOLOGY:What are the next steps in moving this forward?

Topp:

Blinatumomab is approved in the United States, Canada, Australia, and many European countries for relapsed and refractory ALL. This confirms (and some of these approvals are based convivially on this phase III trial) that it will, perhaps, be established as the standard therapy for patients with relapsed and refractory ALL.

With an agent that is so potent, and that has this kind of toxicity profile, the question will be how we will be able to integrate that into frontline therapy. Those kinds of trials are on the way, both in America as well as in Europe, in patients with PH-negative ALL and in patients with PH-positive ALL. We hope that blinatumomab can improve survival of ALL patients in the frontline setting.

Moreover, blinatumomab has been tested in children and has been shown to be an effective therapy. Obviously a therapy that is both active and non-chemotherapy is extremely attractive as a treatment for children, as these types of patients are hurt by chemotherapy in their development. That is something that has to be done perfectly in clinical trials.

TARGETED ONCOLOGY:Are there any therapies that could potentially be integrated into the frontline?

Topp:

inotuzumab

I think we are seeing maybe 2 agents in ALL that can be integrated into frontline therapy. There is, a C22 conjugate with tagged on chemotherapy, and then there’s blinatumomab. Both can't be integrated into therapy and, on one hand, increase the response rate, and also the survival rate, but detoxify the therapy for the patients as well. So, it's possible to integrate that into frontline therapy and to combine them.