TMI Shows Potential Over Traditional TBI in Hematologic Malignancies

Colton Ladbury, MD

In the evolving landscape of radiation therapy for hematologic malignancies, total marrow irradiation (TMI) is becoming a safe and more targeted alternative to traditional total body irradiation (TBI), according to findings presented during the American Society for Radiation Oncology (ASTRO) Annual Meeting.

Colton Ladbury, MD, explained some of the significant benefits of TMI. These include its ability to focus radiation on the bone marrow and lymph nodes, spare healthy tissues, and reduce long-term toxicities.

In the presentation, findings from a study that monitored patients after transplantation for late toxicities, including hypothyroidism, cataracts, and lung infections were discussed. While there can be challenges with implementing these findings into practice, Ladbury emphasized the importance of continuing to monitor patients even after the cancer is in remission.

In an interview with Targeted Oncology^TM, Ladbury discussed new insights from the study and expanded on TMI’s potential to transform transplant conditioning.

Multipotent stem cells in the bone marrow: © Juan Gärtner - stock.adobe.com

Targeted Oncology: Can you provide an overview of this abstract being presented at ASTRO?

Ladbury: Radiation has been used historically as part of the conditioning regimen for patients undergoing transplants for hematologic malignancies. That has been done for decades. It is very nontargeted, called total body irradiation for a reason as it treats the entire body. At City of Hope, somewhere around 2006, we started a different technique called total marrow irradiation where they thought, [if a patient has] leukemia, we do not need to treat the entire body. We probably need to just focus on either the bone marrow plus or minus the lymph nodes. Around that time, there were advances in radiation technology that made it possible to focus on those parts and spare other parts of the body. That was something that we have been doing more of since we can decrease toxicities by not giving radiation to the parts of the body that do not necessarily need it, and by not having as much toxicity, we may be able to go to a higher dose of radiation, which may have better efficacy against leukemia.

This was all theoretical at first. We previously looked at a small group of patients who have been treated with TMI to look at their toxicities, but what this abstract was trying to do is double that number of patients and have a little bit more long-term follow-up to look at if we are reducing toxicity compared with historical controls, and what are the unmet needs that we still need to look for in terms of long-term toxicities?

What are some of the most common toxicities observed among patients who have undergone TMI transplant conditioning regimens?

It is an interesting and challenging question. This technique previously was done just for patients who did not achieve a complete remission to induction chemotherapy. It was mainly [patients] who would not be eligible for transplant otherwise. It was something that was strictly meant to be experimental. All that is meant to say is that it is done in patients who had a relatively poor prognosis. A lot of patients, unfortunately, in the initial studies would not live long enough to develop many late toxicities, only a small minority of them. [However], as we have become more experienced with this, we are expanding this to the point that we're now able to offer it to almost any patient, even the ones that have achieved complete remission. We are now starting to see more of those late toxicities.

In this study, the most common one was cataract formation, which I think occurred in roughly a quarter of patients. That is something we know happens frequently in total body irradiation at higher rates. Now that we have patients that we are treating that have a good prognosis and have a long life expectancy, something like cataract formation is something that can, especially in younger patients, have a significant impact on quality –of life and therefore, it is something we should look out for and monitor for so we can intervene early and effectively.

There are other toxicities. When we look at transplants, the main toxicity we worry about is pneumonitis, which happens in a minority of patients with TBI, but it is not a small number. In this study with the TMI, 0 or 1 patient out of the several hundred patients experienced pneumonitis, so a dramatic decrease, but we do still see that a large number of patients still go on, especially in the first few years, to experience respiratory infections, probably related to decreased immune function in the lungs following TMI related to the low doses. We do see that by limiting the dose to the lungs, we can decrease those rates slightly. Again, something common, something we can handle, but that we now have the techniques to mitigate more on some of these patients.

How do these findings change your approach to patient management and follow-up care?

This has been almost a 20-year process of showing that this is something that works. Now, we have further data that says, not in a head-to-head comparison, but based on historical controls, that TMI is dramatically less toxic than standard TBI. When you look at other studies, it seems to be quite effective, probably just as effective as TMI and or TBI, and it does not have the same drawbacks. I think what this is saying is we are ready for the prime time, and we are ready for this to be part of a standard-of-care treatment for transplants.

At City of Hope, we have trials now for patients who are in complete remission, who otherwise would just be getting TBI. We are looking into running phase 3 trials to be able to compare this to TBI. We are also working on making this available off protocol just as a standard-of-care option at City of Hope for patients. All this data was collected as part of a protocol, where we reminded the hematologist during their annual follow-ups to check for all these other toxicities. I think it emphasizes that we still need to keep doing that, even potentially past the 8 years that this protocol asked to look for these late toxicities. Patients that now are living longer and have the time to develop these things. Their cancer is gone, but they are living with the sequela of it. So, checking for hypothyroidism, cataracts, sexual function, hormone levels, and other things that we do not have the data on. These thingsimpact quality –of life in these patients, [and] we need to be checking on an annual basis now that cancer is not as big of a worry anymore.

Would these findings change screening and monitoring recommendations that you would add to routine clinic clinical care?

There is a challenge for all patients and then getting lost to follow-up. But I think most of these screenings that we did, as far as this protocol, would be something that already would be recommended for the standard transplant patient. We should be monitoring blood work, we should be doing opthamalogic examinations, and we should be monitoring for signs of infection, pneumonia, and things like that. I do not know if it changes anything from that standpoint, but it just emphasizes the need to try to do everything we can, so patients do not get lost to follow-up so that when there is toxicity that is attributable to us, we can do something about it before it gets much more difficult to treat and has a much bigger impact on quality of life.

How do you counsel patients about the potential risks of late toxicities when considering these regimens?

We have used the previous paper, and now we will be able to use this abstract. A transplant is no small feat, and it is a big deal and has a lot of toxicities, both from the radiation as well as from chemotherapy and other conditioning regimens. We still tell patients to expect a lot of toxicities, though, from the radiation standpoint, we can say that typically they are very manageable. As far as the late toxicities,there is still a sizable chance that you will have some sort of [adverse] effect. For cataracts, the cumulative incidence was 25%, so a quarter of patients experienced that, and the cumulative incidence of lung infection was 35.4%. These are not small numbers, but we can then say, compared with what we used to do, it is still lower. We are still doing everything we can to limit [the] risk of toxicity. We have good approaches to managing them if they do happen. For example, cataracts are annoying, but they are not life threatening, and they are something that we can easily treat as long as we catch them early. I mainly take that as an opportunity to say, yes, it can happen, [but] it is less likely than historically. [And] if it does happen, as long as we keep a close eye on you, we can treat them effectively.

Are there any specific patient populations who might be at higher risk for developing late toxicities?

It is a challenge because it is still a small subset, and the number of patients who have an event is low. It is difficult to do this kind of predictive modeling of which subsets or demographics might have an increased risk of some of these toxicities. We do show in the abstract that patients who can get a higher dose of radiation to the lung do have an increased risk of developing lung infections in the future. That is an easy one. But others that I would say are not necessarily someone that we are definitely at an increased risk, but something we need to look out more for, is, as we are adding more younger patients, as we are having patients that have [better and better] prognoses, those are the patients that are going to be able to go on and develop these late toxicities. As we are expanding the patient population to those patients that are relatively lower risk, I think looking for these toxicities becomes even more important.

Are there any challenges you anticipate when implementing these findings into practice?

The number one challenge is that still, patients are being lost to follow-up. Even with these patients that were on the trial, there were several parts of the toxicity in individual patients that were incomplete. I think even if a patient is coming in to see their hematologist, they may not be going to see an eye doctor to get checked for cataracts. They may not be getting all these screenings that might be helpful. I think it is just something that I emphasize with patients at every single visit to basically have a checklist to make sure that they are getting all the screenings that would be helpful for them.

What kind of collaboration with other health care providers might help in managing these toxicities?

We now have compelling data that the toxicity is certainly no worse than standard TBI and almost certainly is better, although we do not have a randomized head-to-head comparison. Whether or not that is compelling enough for someone to say, TMI can be a standard-of-care option for patients will depend on the practitioner. One possibility is, as I mentioned before, that we are looking into the possibility of randomized trials that we can then compare them head –to head and show, hopefully, that indeed, the late toxicities are decreased by being more focused, as we would anticipate. I think that is an opportunity for further study.

We are going to continue to follow the patients that we treat again and see if anything changes. I think one thing that was interesting with this abstract is what changed from the previous study. It was about 8 years ago that it was published, and the rate of cataracts, I think, was underreported in that study. They did significantly increase in this study. It is something that, even though it is what the data looks like right now, [we need] to continue to look at the data and make sure that nothing is changing [unexpectedly]. We are looking at the other physicians, nurses, and case managers who are involved with the transplants, and at the end of the day, when we are looking at who is seeing these patients most commonly in follow-up, it is not us, the radiation oncologists, but it is the hematologist. So, working with them to educate on the possible toxicities related to radiation, how to look out for it, how to address it, and when to send them back to us to see if there is something we can help with in terms of managing toxicities, is something we can help do to make sure that the follow-up care for these patients is optimized.

In the future, we will have more data. The big concern in addition to decreasing toxicity is that when we are decreasing toxicity, we are making sure that we are not causing an increased risk of relapse outside of the bone marrow where we are intentionally not treating. That is one of the big concerns with TMI. We have some data that suggests that it is not an increased risk. We are working on rationale, reanalyzing this whole larger patient population to kind of confirm that. I think these are the two main things that need to be shown before we make this a full kind of standard option.