A novel approach combining total marrow and lymphoid irradiation (TMLI) with post-transplant cyclophosphamide (PTCy) has demonstrated exceptional outcomes for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), according to findings presented at the 2025 Tandem Meetings.
The phase 1 trial (NCT03467386) enrolled 34 patients aged 18 to 60 years with AML in first or second complete remission who were minimal residual disease (MRD)-negative and had matched donors. At a median follow-up of 24.1 months for surviving patients, the results showed impressive 2-year overall survival and leukemia-free survival rates of 84% and 85%, respectively.
Innovative Approach Addresses Key Transplant Challenges
The study was designed to tackle two major challenges in transplantation: disease relapse and chronic graft-versus-host disease (GVHD). The innovative protocol delivered TMLI at a dose of 20 Gy to disease sites, while capping exposure at 12 Gy for brain and liver, and further sparing other organs (2.6 Gy to 10.4 Gy).
"The two major causes of failure in the transplant setting are basically relapse and chronic graft-vs-host disease," explained Anthony S. Stein, MD, professor and co-director of the acute leukemia program at City of Hope. "In this study, we devised a plan to address both issues."
The approach incorporated PTCy administered on days 3 and 4 post-transplant, followed by tacrolimus, which was tapered from day 90 if no GVHD occurred. This strategy aimed to limit chronic GVHD while using targeted higher-dose radiation to prevent the potential increased relapse risk associated with additional immunosuppression.
Remarkable Safety Profile
Perhaps most striking in the results was the complete absence of non-relapse mortality, with no deaths attributed to treatment toxicity or GVHD complications. All patients achieved successful engraftment, and no grade 3 or 4 Bearman toxicities were observed.
The incidence of chronic GVHD was remarkably low at 15%, with only 4 patients requiring systemic therapy. GVHD-free, relapse-free survival rates were 71% at 1 year and 67% at 2 years.
"We did not see any grade 3 or 4 pulmonary toxicities. The toxicity profile is much better compared to regular radiation therapy," Dr. Stein noted. "Patients develop a lot less mucositis and also develop a lot less GI toxicities, such as diarrhea. And because of less radiation exposure and toxicity to the GI tract, we've also seen fewer episodes of bacteremias and infections."
Technical Advantages of TMLI
The TMLI approach represents a significant advancement over conventional total body irradiation (TBI). By precisely targeting radiation to the skeletal system where leukemia cells primarily reside, while minimizing exposure to healthy tissues, TMLI enables delivery of higher therapeutic doses with fewer side effects.
"When we use TMLI, it enables us to give the maximum dose of radiation to the skeletal system, where the leukemia resides, while giving normal organs much lower doses of radiation," Dr. Stein explained. "For example, we are able to give the gastrointestinal tract only 6 Gy of radiation therapy, and that probably limits the damage to the GI tract and ultimately the homing of T cells to the GI tract."
This targeted approach builds on earlier research from the 1990s that showed improved relapse-free survival with higher radiation doses (1575 cGy vs. 1200 cGy), but without overall survival benefits due to increased toxicity. TMLI appears to overcome this limitation by allowing for dose escalation without corresponding increases in toxicity.
Freedom from Immunosuppression
A particularly meaningful outcome for patients was the ability to discontinue immunosuppressive medications. According to Dr. Stein, all study participants were able to stop immunosuppression therapy, most within three years post-transplant.
"Most of our patients are off all their immunosuppression by 3 years post-transplant, as opposed to being on lifelong immunosuppression to manage chronic GVHD," he said. "And also, by doing this, we have shown that we are not seeing any increased risk of relapse by decreasing the risk of chronic GVHD."
This represents a significant quality-of-life improvement for transplant recipients, who traditionally face the burden of long-term immunosuppression and its associated complications.
Future Directions
Based on these promising results, the research team plans to expand the current study to include a total of 55 patients. They are also proposing a randomized phase 2 trial comparing this approach to standard radiation therapy.
City of Hope is conducting additional TMLI studies across various patient populations, including older patients with persistent disease or MRD-positive disease, haploidentical transplant recipients, and patients with lymphoma.
"I think we have made transplant—at least for AML in first and second remission—a lot safer and also given these patients, at 2 years, an 85% leukemia-free survival," Dr. Stein concluded. "I am not sure there are many treatments—I do not think there are too many other treatments—that can give such good results."
For community oncologists, these findings suggest that allogeneic transplantation for AML may be evolving toward a safer and more effective intervention, potentially expanding the population of patients who might benefit from this potentially curative approach.
