Molecular Risk Stratification and Treatment Optimization in Acute Lymphoblastic Leukemia
At the 2026 LL&M Winter Symposium in Amelia Island, Florida, James Foran, MD, Mayo Clinic, Jacksonville, Florida, provides an update on the evolving treatment landscape for adult patients with acute lymphoblastic leukemia (ALL).
Dr Foran highlights advances in molecular classification and risk stratification, emphasizing the growing role of genomic profiling and the emergence of chemotherapy-free regimens, particularly ponatinib plus blinatumomab, as a new standard of care in Philadelphia-positive ALL. He also discusses the expanding role of blinatumomab, treatment optimization in older and high-risk patients, and the importance of collaboration and clinical trials to improve outcomes.
Transcript:
My name is James Foran, I work at the Mayo Clinic based in Jacksonville, Florida, and I'm delighted to be here attending the 2026 LL&M Winter Symposium on Amelia Island near Fernandina Beach. It's sunny, it's pretty here. It's a little colder than I thought it would be, although I live nearby, so I guess that goes with the territory.
I've just given a 2026 update on acute lymphoblastic leukemia [ALL] in adults. We discussed the epidemiology of the disease, really, it's much more common in people under the age of 20 and yet it's the older adults who really struggle to get through treatment. The median age of diagnosis is 17, the median age for a patient when they die is 60. So it's the older patients—they have harder leukemias, harder to treat.
I gave a presentation on the updates in classification. Genomics have helped a lot in understanding risk groups in adult ALL, and we now have more than 17 different risk groups on a molecular level. The problem is that many labs aren't designed with RNA sequencing and gene expression profiling to help delineate some of those rare entities—the DUX4-rearranged, the PAX5-altered, the IKAROS-plus prognostic groups that can happen with Philadelphia-positive. So, I think it behooves us all to try to make sure our patients are getting access to the really modern technology it takes to get the risk group right.
Big changes in the disease are the advent of chemotherapy-free regimens, particularly in Philadelphia-positive ALL. We've known for some time it's feasible to do that, there have been really good Italian series called the D-ALBA study that has reported long-term outcomes, the very compelling data from MD Anderson of ponatinib and blinatumomab, but we now have the GIMEMA ALL2820 results, recently presented at ASH, that show a survival advantage, an actual remission and survival advantage. It met its primary end point in a phase 3 randomized study that was 2:1 of chemotherapy-free versus chemotherapy with imatinib, and the chemotherapy-free was ponatinib and blinatumomab, similar to the MD Anderson strategy and we're seeing a survival advantage. I think that really is the new standard of care for adults with Philadelphia-positive ALL.
We know for MRD-negative ALL, based upon the E1910 study published just over a year ago by Mark Litzow, that even MRD-negative benefits from 4 cycles interspersed with blinatumomab to improve overall survival. Blinatumomab is not just an MRD eraser now, it's even in MRD-negative that it matters.
In older patients with ALL, there are very effective chemotherapy combinations that are now dose-reduced. We don't have to use the EWALL protocols or some of the other low-intensity protocols, like the EWALL. Mini–Hyper-CVAD or mini-CVD, alternating with mini–methotrexate and cytarabine with inotuzumab, is getting very high remission rates and durable remissions– excellent results, well tolerated. There is a pilot study by the Alliance that I presented, or at least I gave an update on, recently published by Matt Wieduwilt, that showed you can go chemotherapy-free with sequential inotuzumab and blinatumomab. And you have good remission rates, and you've got good event-free survival and overall survival. I just think we need, personally, more data before we go chemotherapy-free for older Philadelphia-negative ALL.
I did review the prognosis of other high-risk entities—secondary ALL, Philadelphia-like ALL, TP53-positive. Even if they're MRD-negative, I'm not sure we can get away from allogeneic transplants in those patients yet. There's some early data that maybe they can get long-term remission without that, but I'd like to see more robust data. But certainly in Philadelphia-positive ALL, if you get MRD-negative, that's its own complication. Is that MRD defined by BCR-ABL, by ClonoSEQ, or even by flow cytometry? But if you're BCR-ABL negative, especially early on after therapy, I don't think there's an ongoing advantage of an allogeneic transplant for the MRD-negative population, and I think the field's moving away from that.
Finally, I think the community needs to continue to come together, work together. The pediatric oncologists and hematologists are very coordinated through the Children's Oncology Group in their studies and regimented, and they get excellent outcomes. The field is moving that way for us too, and the more we collaborate, the more we share data, the more we share protocols, and continue to emphasize clinical trials, the better outcomes we're going to get for our patients.
Source:
Foran J. Evolving management of ALL: Integrating 2025 data into 2026 practice. Presented at Lymphoma, Leukemia & Myeloma Winter Symposium; January 30 - February 1, 2026. Amelia Island, Florida.
