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Blinatumomab for ALL MRD
Treatment of Acute Lymphoblastic Leukemia Measurable Residual Disease Using Blinatumomab

Released: September 28, 2018

Expiration: September 27, 2019

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What Is MRD and Why Is It Important in ALL?
Many patients with acute lymphoblastic leukemia (ALL) achieve a CR but have residual leukemia blasts < 5%. We have learned that this measurable residual disease (also known as minimal residual disease, or MRD) is prognostic for leukemia relapsing. There are now several testing methods that allow doctors to quantify MRD down to as few as one leukemia cell among one million white blood cells (0.0001% or 10-6), which dramatically improves the ability to monitor how well individual patients are responding to chemotherapy treatment. Many studies have shown that having MRD at a level higher than one leukemia cell in 10,000 white blood cells (0.01% or 10-4) is highly associated with relapse risk, and thus, this is a patient population that requires new approaches to prevent them from relapsing.

What Is Blinatumomab and How Does It Work?
Blinatumomab is a bispecific T-cell engager that was designed to bind CD19 on the surface of B-cell ALL blasts and to CD3 on the surface of T-cells. When an ALL blast is brought into close proximity to a T-cell with blinatumomab, the T-cell will be activated and will kill the leukemia cell. This is a type of immunotherapy because it relies on the function of cells in the patient’s own immune system to help eliminate cancer cells. Blinatumomab was originally approved for use in the United States in 2014 for patients with relapsed or refractory B-cell ALL. Recently, the FDA gave accelerated approval for treatment with blinatumomab in B-cell precursor ALL in first or second CR with MRD ≥ 0.1%.

How Is Blinatumomab Given?
Blinatumomab has a relatively short half-life of 2.1 hours, which requires it to be continuously infused using a portable pump for 28 consecutive days. Patients will generally be admitted to the hospital for the first few days of treatment and discharged to continue the remainder of the 28 days of therapy as an outpatient with regular follow-up in clinic to monitor labs and to check for toxicities of treatment.

Can Blinatumomab Eliminate MRD in ALL?
Due to the novel mechanism of action, blinatumomab was tested very early in its development as a potential treatment for MRD. A pilot study with 20 evaluable patients was originally reported in 2011 and demonstrated that 16 of those patients became MRD negative (defined in this study as no leukemia cells detectable with a sensitivity of 0.01% or one leukemia in 10,000 white blood cells), which represents an 80% efficacy rate. Of interest, all patients responded in the first cycle of blinatumomab treatment. When that study was first reported, it also demonstrated that 78% of patients remained leukemia free with follow-up of at least 1 year in most patients. A follow-up report on that initial study revealed that one half of the patients remained in remission as long as 5 years after the blinatumomab treatment; among those 10 patients, 5 had undergone allogeneic stem cell transplantation and 5 had not.

A subsequent, larger study enrolled 113 evaluable patients to receive up to four 28-day cycles of blinatumomab for MRD > 0.1% after 3 cycles of conventional multiagent chemotherapy. Remarkably, the success rate for rendering patients MRD negative (defined similarly to the pilot study as no leukemia cells detectable with a sensitivity of 0.01%) was 78%—almost exactly the same as the initial pilot study. The leukemia-free survival in this study was 54% at 18 months and OS was 3 years from starting blinatumomab was 50%. Outcomes were best in patients who received blinatumomab for MRD during their first remission, as opposed to subsequent remissions. Approximately 3 out of 4 patients in this study proceeded to allogeneic stem cell transplantation, so that may have contributed to long-term survival, but there were some patients who remained in remission without transplantation after blinatumomab treatment.

Recently, a long-term follow-up of patients with B-cell precursor ALL in continuous CR by Topp and colleagues of suggests potential OS benefit from sequential treatment with blinatumomab followed by stem cell transplantation, particularly in patients with MRD-positive ALL or aged 35 years or younger. It remains unknown whether transplantation is required for all patients rendered MRD negative using blinatumomab, but studies are under way to better understand the best way to treat patients.

Are There Risks With Blinatumomab Treatment?
Since blinatumomab activates immune cells, some patients may experience adverse events. The adverse events of blinatumomab are less severe when used for MRD than they are when the drug is used to treat patients in fulminant relapse. Most patients will experience a fever during treatment with blinatumomab, but this is rarely severe and is infrequently associated with more significant symptoms. Up to 15% of patients may experience a temporary drop in their normal blood counts. Blinatumomab can also be associated with neurologic adverse events. When used in the MRD setting, these tend to be minor and easily manageable, but up to 30% of patients may experience a tremor (severe in fewer than 5%), 13% may experience aphasia or word-finding difficulty (severe in 1%), and 5% may become confused (severe in 1%). Adverse events typically resolve within 4 days of stopping the blinatumomab infusion.

Conclusion
We now have new tools that can help significantly improve leukemia-free survival and OS for patients with ALL. Of importance, MRD quantification methods allow better treatment response monitoring of individual patients and the identification of those who are at increased risk for relapse based on the detection of MRD after chemotherapy. For the first time, the FDA recognized the presence of MRD as a reasonable indication for therapy, and blinatumomab can now be used to render 4 out of 5 MRD-positive patients MRD negative. Achieving an MRD-negative remission is critically important for leukemia-free survival and enables patients to go on to transplantation with the highest chance of success or to alternative maintenance treatments in patients for whom transplantation is not possible.

Your Thoughts
Are you using blinatumomab in your practice? Please leave a comment below about your experiences or questions that you may have about using blinatumomab in practice.

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