How Blinatumomab Changed the Standard of Care for B-ALL

B-cell acute lymphoblastic leukemia, or B-ALL, is not only the most common childhood cancer, but one of the most curable. Roughly 85% of kids who are diagnosed go into remission and remain cancer-free. But the chemotherapy patients undergo can wreak havoc, causing nausea and vomiting, blood clots, liver toxicity and infections. These side effects can be severe during treatment and may also lead to problems for the remainder of their long lives. 

“Chemotherapy sometimes feels like Drano,” says Lia Gore, MD, Children’s Hospital Colorado hematologist/oncologist. “It gets rid of everything in its path, including healthy cells.”

Kids who undergo chemotherapy at a young age can face adverse effects that last decades. The treatment impacts bone mineral metabolism — which can cause joint damage in teenagers that may necessitate hip and knee replacements when they become young adults. Depending on the particular drugs used, chemotherapy can, in rare cases, cause metabolic syndrome, impact fertility, damage the heart and lead to pancreatitis. So, while the patient may be cured of B-ALL, they could still spend many years facing  complications. 

But where chemotherapy causes unchecked destruction, blinatumomab, an immunotherapy drug created in a research lab in Munich, Germany, more than a decade ago, is more precise in its attack. Over the course of the last 15 years, researchers at Children’s Colorado and across the globe have repeatedly proven its efficacy in treating B-ALL more effectively with fewer negative effects. 

How blinatumomab works

Instead of fighting cancer with fire, immunotherapies like blinatumomab give the body’s own defense a boost. In this case, the drug acts as a connector. It is designed to attach to immune system T cells on one end and a protein called CD19 on the other. CD19 is very commonly found on the surface of B cell lymphoblasts. In B-ALL, these lymphoblasts malfunction causing them to become cancerous. 

“It is engineered to link a patient’s T cells to CD19 on the leukemia cells, and it's like a magnet that brings these two cells in proximity to each other,” Dr. Gore explains. “That's all it has to do, because the body's immune system is smart enough to take over, killing the leukemia cells, and it can do that much more selectively, much more specifically and much more effectively than any of our chemotherapies.”

In the process, some healthy B cells are killed as well, but that side effect is easily remedied through supportive care. For most patients, the normal B cells eventually recover. While there are some rare side effects with blinatumomab related to activation of the immune system, they are usually manageable with supportive care, and most patients report feeling energetic and well while receiving the drug. 

Becoming a frontline treatment

Testing for blinatumomab began back in 2009 and was led by the Children’s Oncology Group (COG) along with European collaborators. COG is a National Cancer Institute-funded cooperative group and is the world’s largest organization devoted exclusively to childhood and adolescent cancer research. The group unites more than 10,000 experts in childhood cancer at more than 220 leading children’s hospitals, universities and cancer centers across North America, Australia, New Zealand and Saudi Arabia. COG’s mission is to improve the cure rate and outcomes for all children with cancer. Dr. Gore served as the principal investigator (PI) for the initial blinatumomab trial, known as AALL1121, which ran across 20 COG member hospitals, including Children’s Colorado.

At the time, the experimental drug, which had shown great promise in preclinical trials, was only available to patients with B-ALL who had relapsed multiple times and tried a whole host of therapies. These kids had only a 5% to 10% chance of survival when they enrolled, but for patients on the AALL1121 trial, that grew to 39%.

With this information in hand, the international team moved the drug into a new population: Kids who had relapsed only once. During this phase of the work, Dr. Gore served as a mentor to a new COG PI for this trial, while other members of the Children’s Colorado team acted as educators to multiple study sites, guiding nurses, clinicians and researchers on the drug’s administration and other critical tasks. The team included now-retired Deb Schissel, RN, who served as an RN research coordinator; Kelly Maloney, MD, who served as site PI; and Margaret Macy, MD, head of the Children’s Colorado Experimental Therapeutics Program; among countless others. 

Once again, the new trial’s results were stunning: “Better outcomes, less toxicity, fewer infections — all the kinds of things that you want to see,” Dr. Gore says. “And as we were starting to get data and results, we had to say, ‘Wow, this is better than we had hoped. Can we bring it to all children with B-ALL?’”

That’s when blinatumomab became a frontline treatment. In 2017, the trial, known as COG AALL1731, began enrolling kids 1 to 9 years of age who would receive the drug as one component of multiagent therapy for B-ALL. It was delivered in two treatment blocks, alternating with traditional chemotherapy. The trial was closed early when results showed a decrease in the risk of relapse by 60% for kids who received blinatumomab as a part of their treatment.

“We thought that the difference in outcomes between the experimental group who received chemotherapy plus blinatumomab and the standard group who received chemotherapy only would not happen as quickly and would not be as obvious,” Dr. Gore recalls. “We were caught off guard by the AALL1731 results last summer. Honestly, it came out of nowhere to us. We anticipated it would be at least two more years before we would have those results.”

Today, after multiple trials and decades of work that spanned the entire globe, blinatumomab is the new standard of care when given with chemotherapy for most children with B-ALL.

Next up, more research.

The Children’s Colorado leukemia team is already spinning with new questions: “How else can we use blinatumomab for other subsets of patients? How can we reduce other drugs with really significant side effects? Can we use it for patients in bone marrow transplant differently? Can we use it to help deepen remission for patients that have more aggressive disease and may relapse early or for those who do not tolerate standard chemotherapy? Can we use it with other targeted drugs so that we can reduce the traditional cytotoxic chemotherapies, and how do we do that?”

The team is also investigating how to improve access to the drug, which must be given through a continuous IV infusion over the course of 28 days. Kids must always wear a backpack with the drug during that period and must remain close enough to a hospital where they can get refills. For kids in rural areas, this is particularly difficult, and the burden on families is significant regardless of where they live. The team will soon participate in a multicenter trial to test a new delivery system for the drug that requires shots rather than continuous infusion.

The village behind blinatumomab

In addition to Drs. Gore, Maloney and Macy, and nurse coordinator Schissel, the Children’s Colorado team behind this therapy has been extensive and evolving. On her very first day at Children’s Colorado, Melissa Widener, PA-C, delivered blinatumomab to a patient, and her work hasn’t stopped since. And just last year, Maureen O’Brien, MD, who led blinatumomab research for years at Cincinnati Children's Hospital Medical Center, officially joined the group at Children’s Colorado. 

According to Dr. O’Brien, it was the careful and compassionate teamwork across thousands of people and literal oceans that has made all the difference.  

“This is not possible to do without a huge number of people involved, ranging from the regulatory specialists and the clinical research associates who are working with the consents and collecting the data and the physicians who are treating them and the nurses and the investigational pharmacy,” she says. “It really requires everybody being on the same page and of constant re-education.”

Critical to the team as well were all the patients and families who joined in on the study, both to improve their own care and that of others. 

“Really, this is thanks to all the families who were a bit courageous to say, ‘Yes, I am going to do this, I am going to put my toddler into this trial and I'm going to figure it out,’” Dr. Maloney says. “It is the families that said yes and enrolled their kids in it.”

This symphony of collaboration between clinicians, patients, researchers, pharmaceutical companies and more has forever altered the standard of care for the single most common type of cancer in kids, not only improving their chances of survival, but also their long-term quality of life. For Schissel, it was a dream job made flesh. For Widener, it is the perfect example of what can happen when thousands of people unite to realize a truly incredible goal. 

 “When it's with kids and it's with new drugs, so much of the ego comes out,” Widener says. “I work with so many incredibly smart and talented physicians, and I know that every one of them has sat down and entered data into a database and filled out the forms. It is such a team mentality. Everybody is doing the same work. It's all hands on deck. We're always all willing to jump in and do what's needed because it's in service of getting it right.”