TMLI Trial Shows Potential in Relapsed/Refractory Leukemia

Jeffrey Wong, MD

A phase 2 trial is exploring the combination of total marrow and lymphoid irradiation (TMLI) with cyclophosphamide and etoposide for the treatment of patients with high-risk acute leukemia, aiming to address a critical unmet need in the relapsed/refractory leukemia space.

The trial is looking to target leukemia more precisely while minimizing damage to healthy organs, potentially offering a new avenue for patients who have not been considered candidates for stem cell transplantation in the past.

The motivation behind this trial stems from the dismal outcomes that typically are associated with this patient population. As many patients with relapsed/refractory leukemia are excluded from transplantation due to high risks, experts like Jeffrey Wong, MD, and Anthony Stein, MD, look to improve this by using TMLI.

So far, the trial’s results have been promising, showing improved survival rates and lower nonrelapse mortality compared with historical data, and looking ahead, Wong and Stein hope this method might eventually replace total body irradiation in broader clinical practice.

In an interview with Targeted Oncology^TM, Wong, a professor of radiation oncology at City of Hope (COH) Medical Center, and Stein, professor of hematology and stem cell transplantation at COH, provided an in-depth discussion on this phase 2 trial.

Anthony Stein, MD

Targeted Oncology: Please explain the motivation behind conducting this phase 2 trial.

Stein: Patients with relapsed/refractory leukemia have a very poor outcome. Many stem cell transplant centers do exclude these patients from transplant once this active disease is present. Basically, there was a study that was done back in the 1990s in Seattle where they showed that while they increased the total body irradiation, they found a much lower relapse rate with a higher dose of radiation. But unfortunately, there was not an improved survival because of increased toxicity from the higher dose of radiation. Together, we are able to target a higher dose of radiation to the skeletal system where leukemia resides and lower the dose of radiation to normal organs. We started several protocols trying to explore this to see if patients would benefit from using this form of precision- or targeted-based radiation therapy in the setting of a stem cell transplant.

Wong: Radiation therapy is an important part of bone marrow transplantation, which can be a curative procedure for many patients with acute leukemia. Total body irradiation uses a single beam to cover the entire body to deliver the dose, so it is challenging to go through for many patients, and you cannot increase the dose, as Dr. Stein mentioned. Technology came to the field of radiation oncology, that instead of delivering the dose in a single beam, literally hundreds of tiny laser-like beamlets, treatment can be computer controlled and targeted to only certain parts of the body. Therefore, we were able to deliver a more targeted form of radiation therapy that allowed us to reduce the doses to the normal organs and reduce [adverse] effects. It made it feasible to escalate the dose to the doses that we have on this trial. This trial demonstrates the feasibility and promise of this particular approach.

How does this treatment differ from standard treatment protocols for this patient population?

Stein: Most patients with active leukemia will not be transplanted in the majority of centers across the US and in Europe. Standard transplant regimens are usually using a chemotherapy-based regimen. But currently, most of the patients with active leukemia are not transplanted.

Wong: The patients with disease that cannot get into remission are challenging. They do not have transplant options. This provides a promising transplant option for them, again, to be able to deliver targeted radiation therapy at a higher dose has resulted in some promising results. This contrasts with patients that can get into remission that can get a transplant, but this particular subset of patients with active disease who cannot get into remission now have this particular approach as a possible option for them.

Can you discuss the methods and design of the trial?

Stein: We initially did a phase 1 study. We started at a dose of 1200 [cGy], with dose escalation up to 2000 [cGy], together with cyclophosphamide and etoposide, and we reached a dose of 2000 cGy without finding a dose-limiting toxicity. But at the 2000 [cGy] dose, we found that if we increase the dose of TMLI beyond 2000, we will not be able to protect the normal organs. Those organs would then be exposed to normal doses of radiation that they would receive with [total body irradiation (TBI)] and will probably result in a higher mortality rate, which will be going back to the Seattle study done in the 1990s.

Based on that phase 1 study, we have now moved to this study, which is phase 2 study, where again, the main group was patients with relapsed/refractory leukemia. All patients receive the standard dose of TMLI 2000, cyclophosphamide, and etoposide. All patients receive Nab-sirolimus [Fyarro; ABI-009] for [graft-vs-host disease (GVHD)] prevention. There was other supportive care to prevent infections, to prevent any sinusoidal obstructive disease, and to prevent tumor lysis as these patients had active disease when they started the radiation treatment.

Wong: I can comment also on other end points that were important for this study, especially regarding methodology. This is a new way to deliver targeted radiation therapy to a patient undergoing transplant. This trial demonstrates it is feasible, and it can be done safely, and it can improve efficacy of the treatments and the conditioning prior to transplant. Using this technology, and this particular approach, we found that we were able to reduce the doses to the normal organs by approximately 25% to 50% of the doses to the bone marrow. As Dr. Stein mentioned that the doses to the bone marrow are to 2000 cGy so the normal organs are getting much less than that dose. In addition, we demonstrated that the [adverse] effects and the toxicities that have been normally associated with radiation in the form of total body irradiation or TBI are much less with this particular approach. All of those end points were addressed in this particular study.

What were the most notable findings?

Stein: The regimen was relatively well tolerated in this high-risk group of patients being transplanted with active leukemia. Our nonrelapse mortality rate was around 10%, and 1- or 2-year overall survival and progression free survival [data were] much better than what was previously seen with standard transplant regiments. The last time we did a randomized study, I think back in the early 2000s, 2-year, 3-year survival was less than 20%. That is why a lot of centers stopped doing transplants for patients with relapsed/refractory disease.

Wong: Our outcomes are superior to what had been reported historically, as Dr. Stein mentioned. There are also a couple of other questions that we feel that this trial has addressed. One, there was some concern when we initially started this effort using a targeted form of radiation instead of TBI. There was concern that the relapse rates would be higher because of this sparing radiation doses to certain parts of the body and organs. That is not the case. As Dr. Stein mentioned, the relapse rates are lower than what has been historically reported. Another topic or question that is specific to radiation oncology is the concern that the method or the technique of delivering the radiation at a bit higher dose rate could be possibly detrimental in terms of causing more [adverse] effects. We have seen no indication of that. This large experience has addressed those 2 initial questions that were asked at the start of the trial.

What are the next steps for this research?

Stein: For our patients with relapsed/refractory leukemia, we have [treated] just over 100 patients, and we are analyzing all the data and in the process of writing up a manuscript. We also are looking at subgroups of patients to define which patients will benefit from this conditioning regimen and which patients still do not benefit and require further modifications or further clinical trials to improve the outcomes. For instance, we are looking at a number of prior regimens a patient receives, the percent blasts in the bone marrow, percent blasts in a peripheral blood to see is there a cutoff where if it exceeds a certain limit certain level, that the outcome is not good, and then we would make further modifications.

The second point is, because the regimen has been safe with low nonrelapse mortality, we have now moved using total body irradiation to patients with [acute myeloid leukemia (AML)] in first and second remission. We have currently treated about 40 patients. We are planning to enroll up to 55 patients to get a better understanding of the outcome and also the risk of graft-vs-host disease. Hopefully, in the future for patients with AML in first remission, we can have a low relapse rate, nonrelapse mortality, nonrelapse mortality at 2 years of 0%, and also improve the risk of getting chronic graft-vs-host disease where most patients have able to come off the immunosuppressive therapy by 1 year and not beyond lifelong immunosuppressive therapy.

Wong: From a broader perspective, we feel that and would like to see these results translate into interest from other centers. We are seeing more centers adopting this approach. We feel the results of this particular study, when reported, will further increase that interest to have these trials and this approach to be successful. We need to have a strong collaboration between a hematologist and radiation oncologists. My hope is that these trials will encourage my radiation oncology colleagues to look closely at this approach. It is a feasible approach and executable in the clinic and can provide benefit to patients who have limited options. This particular approach has offered options for patients who have limited options who have active disease. Now, we are looking closely at using this same approach in patients who would normally have total body irradiation. Perhaps this approach could eventually replace total body irradiation, but more work needs to be done in that area.

REFERENCE:

Phase II trial of TMLI 20 Gy in combination with cyclophosphamide and etoposide in patients with poor-risk acute leukemia. Presented at: 2024 American Society for Therapeutic Radiology and Oncology Annual Meeting; September 29-October 2, 2024; Washington, DC.