Organ-Sparing TMLI Enhances AML Transplant Outcomes

Anthony S. Stein, MD

The combination of total marrow and lymphoid irradiation (TMLI) 20 Gy and post-transplant cyclophosphamide (PTCy) led to improved outcomes when given to patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation (HCT), according to a study presented at the 2025 Tandem Meetings (NCT03467386).¹

The trial included 34 patients aged 18 to 60 who were in first or second complete remission (CR), were minimal residual disease (MRD)-negative, and had matched donors. TMLI was delivered at a dose of 20 Gy to disease sites, capped at 12 Gy for brain and liver, and spared other organs (2.6 Gy to 10.4 Gy). PTCy was administered on days 3 and 4, followed by tacrolimus, tapered from day 90 if no GVHD occurred.

Results showed that at a median follow-up of 24.1 months (range, 5.6-25.4) for surviving patients (n = 30), the 2-year overall survival and leukemia-free survival rates were 84% and 85%, respectively, and the relapse rate was 15%. Non-relapse mortality (NRM) was 0%.

No grade 3 or 4 Bearman toxicities or toxicity-related deaths occurred, and all patients were engrafted. A total of 15% of patients developed chronic graft-vs-host disease (GVHD), with 4 requiring systemic therapy. GVHD-free, relapse-free survival (GRFS) rates were 71% at 1 year and 67% at 2 years.

These findings support further investigation of TMLI and PTCy as a replacement for total body irradiation in HCT.

In an interview with Targeted Oncology^TM, Anthony S. Stein, MD, professor, co-director of the acute leukemia program at City of Hope, further discussed this study exploring TMLI combined with PTCy to improve outcomes for patients with AML undergoing transplants.

Targeted Oncology: Can you provide a brief overview of this study?

Stein: So, a brief overview is that the 2 major causes of failure in the transplant setting are basically relapse and chronic graft-vs-host disease. In this study, we devised a plan to address both issues. One was to add PTCy, given on days 3 and 4, to try and limit the incidence of chronic GVHD. However, by adding this extra immunosuppression and decreasing the risk of GVHD, there is a potential for increased relapse.

A prior study done in the 1990s at Seattle had shown improved relapse-free survival for patients receiving 1575 cGy of radiation, as opposed to 1200 cGy, but overall survival was not affected because of increased toxicity. By using total marrow and lymphoid irradiation [TMLI] in the relapse setting, we have shown that we are able to deliver higher doses of radiation to targeted areas while sparing normal organs. So, the goal of this study was basically to increase the conditioning radiation dose to 2000 cGy, together with post-transplant cyclophosphamide, to address both of those issues.

MIcroscopic image of bone marrow cells - Generated with Google Gemini AI

Who was included in the study, and what were the patient selection criteria?

This is for patients with AML in first and second remission. They had to be MRD-negative and have a fully matched sibling or unrelated donor. The age initially was up to 60, but then we extended it up to 65 because it was very well tolerated.

What were the study's key findings?

The key findings, with a median follow-up now—these are results for the first 34 patients that were treated—the median follow-up for these patients is 2 years, with the range being 5.6 to 25.4 months for surviving patients. Of note, we had no grade 3 to 4 pulmonary toxicities or toxicity-related deaths. No deaths were seen. Our non-relapse mortality at 2 years for the study is 0. So, basically, no patients have died from toxicities related to the regimen or from graft-vs-host disease. The 1- and 2-year estimates of GVHD-free, relapse-free survival were 71% and 67%, respectively. The 2-year overall survival and leukemia-free survival are 84% and 85%.

How does TMLI compare with standard total body irradiation in terms of reducing graft-vs-host disease?

That is a question we've been trying to address. 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. For example, we are able to give the gastrointestinal [GI] 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. We are currently looking at the exact mechanism to see how that may influence the risk of GVHD, especially of the GI system.

What are the key toxicities associated with this approach, and how do they compare with traditional conditioning regimens?

We did not see any grade 3 or 4 pulmonary toxicities. So, the toxicity profile is much better compared to regular radiation therapy. 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.

Are there any ongoing or planned studies to further investigate TMLI in other hematologic malignancies or patient populations?

For this study, we plan to expand the number of patients to a total of 55 patients. And then, we are proposing to do a randomized phase 2 trial comparing this approach to standard radiation therapy. At City of Hope, we have a wide range of TMLI ongoing protocols. We are exploring it in older patients who still have persistent disease or MRD-positive disease. Many transplant centers will not transplant those patients because of their high risk. So, we have ongoing studies where we've looked at adding TMLI to our regular backbone of fludarabine and melphalan.

So far, results have been published, and those results are looking promising. We have also looked at it in the haploidentical setting, and those studies are also ongoing. Additionally, we have a smaller study looking at the role of TMLI for [patients with] lymphoma, where we hope to target the radiation to the involved lymph node areas while sparing normal organs.

For a community oncologist, what are the key takeaways from this research?

The key takeaway is that, in the past, transplant has always been thought of as having a high risk of toxicity, morbidity, and mortality. At least in this study, we can show that, up to the present time, no patients have died from the transplant regimen or from chronic graft-versus-host disease. I did not mention earlier, but we can also show that the majority—in fact, all our patients—have been able to discontinue immunosuppression.

So, 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. 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.

So overall, 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. I am not sure there are many treatments—I do not think there are too many other treatments—that can give such good results.

REFERENCE:

Stein A, Al Malki MM, Yang D, et al. Total marrow and lymphoid irradiation in combination with post-transplant cyclophosphamide-based graft versus host disease prophylaxis confers favorable GvHD-free/relapse-free survival in patients with acute myeloid leukemia in first or second remission. Presented at the 2025 Tandem Meeting; February 12-15, 2025; Honolulu, HI. Presentation ID 145.