Is MRD Negativity the New Benchmark in ALL Treatment Strategies?

Elias Jabbour, MD, an Executive Editor of Blood Cancers Today and a Professor of Leukemia at the University of Texas MD Anderson Cancer Center, joined Chadi Nabhan, MD, MBA, FACP, to discuss the function of measurable residual disease in treating acute lymphoblastic leukemia (ALL) and other progress that has been made in treating patients with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph−) ALL.

On using MRD to guide treatment strategies, he said that, “in acute leukemia, there’s nothing called minimal. One cell is already too much. So for me, there’s no minimal. If you’re seeing minimal disease or one cell—that means you’ll relapse. And you better intervene at this time because you can get [a] better return than [waiting] for full relapse.”

Dr. Jabbour also provided a brief historical perspective on tyrosine kinase inhibitors (TKIs), explaining how the therapies have improved survival outcomes in Ph+ ALL with or without transplantation.

Dr. Jabbour explained that TKIs improved the survival outcome of patients with Ph+ ALL from 10% to 40% with or without transplantation.

“Patients are relapsing because they don’t have a deep response and because it is driven by a mutation that can prevent the binding of the [TKI] in the protein,” he explained. “Therefore, we moved into a circulation of [TKIs] that can deepen the responses and overcome the problem of resistance.”

Combining chemotherapy with ponatinib has shown a 75% survival at five to six years, Dr. Jabbour noted, while a randomized trial has shown ponatinib’s superiority compared with other TKIs. Because ponatinib is more potent, it overcomes resistance by suppressing the emergence of mutations, he explained.

“We showed for the first time that we may not need transplant to be offered to these patients,” Dr. Jabbour said. “It’s practice-changing. The question of the best TKI is solved today for the first time in ALL.”

Dr. Nabhan posed the question of administering first-generation TKIs such as Gleevec and reserving second- and third-generation TKIs for patients who do not respond to the drug. “Is there merit to trying the older generation [therapies] at all?” he asked.

“In acute leukemia, you don’t have multiple chances,” Dr. Jabbour responded. “I will not wait for the relapse. I want to take my drug upfront. I want the deepest response possible and cure my patient.”

Next, Dr. Jabbour discussed the role of immunotherapy, specifically blinatumomab, in Ph+ ALL. A chemotherapy-free combination of ponatinib and blinatumomab led to 90% MRD negativity in the  clinical setting.

“This is unheard of,” he said. “We went from 10% survival to chemotherapy-free for the vast majority.”

Next, the podcast switched gears to Ph- ALL.

Dr. Jabbour discussed a study that integrated immunotherapy upfront rather than waiting for relapse, shortened the chemotherapy duration from eight cycles to four, and added blinatumomab.

“Historically, the survival was only around 60%, and now we’re at 90% survival without intensive chemotherapy,” Dr. Jabbour noted.

Finally, Dr. Nabhan asked what’s on the horizon for new therapies in ALL.

“We’re shortening chemotherapy and that’s good,” Dr. Jabbour responded. “I think [chimeric antigen receptor (CAR) T-cell therapy] should be used earlier rather than later. If CAR-T is being used upfront in minimal disease, you have a chance of a cure. I’m very fortunate to live in a time when the cure of this is happening. I’m so optimistic.”