Ultra-Low Dose of Radiation Shows Promise in Orbital Indolent B-Cell Lymphomas

A 90% complete response rate was demonstrated in patients with orbital indolent B-cell lymphomas when administered an ultra-low dose radiation therapy strategy of 4 Gy in 2 fractions.

Findings come from a phase 2 study led by Chelsea C. Pinnix, MD, PhD, which examined the use of this response-adapted strategy in this patient population. Instead of using higher standard doses, this study evaluated the patients who had a complete response to 4 Gy in 2 fractions, rather than the 24 Gy dose.

The trial included 50 patients with stage I to IV orbital indolent B-cell lymphomas. Patients were treated with 4 Gy in 2 fractions with responses assessed at intervals of 3 months. If patients did not achieve a complete response with the lower dose, an additional 20 Gy was offered to complete the standard dose of 24 Gy of radiation.

Treatment with the ultra-low dose correlated with limited side effects in patients with orbital indolent B-cell lymphomas. Experts believe that this approach has the potential to improve quality of life without limiting efficacy.

“The key takeaway is that this is a paradigm shift, but there is a lot of data before our study to show that 4 Gy in 2 fractions did contribute to excellent responses. There are many retrospective series people can look at to just see the outcome of 4 Gy in 2 fractions in the orbit. While this is a little bit different of an approach, overall, we do have a lot of data endorsing and supporting the high response rates of just 2 fractions” stated Pinnix, associate professor of Radiation Oncology at MD Anderson, in an interview with Targeted OncologyTM.

In the interview, Pinnix discussed the results of this phase 2 study and how these promising results will shift the treatment paradigm of patients with orbital indolent B-cell lymphoma.

Targeted Oncology: What does the current landscape of the indolent B-cell lymphoma look like?

Pinnix: Indolent B-cell lymphoma can impact the orbit and when it does, the most common histology is MALT lymphoma. Other histologies include silica lymphoma, low-grade B-cell lymphoma, unclassifiable, and these are all very slow growing processes. Patients often will present months, sometimes years, after initial symptoms, reinforcing the slow progress of the disease clinically over time. Once the diagnosis is made, if the disease is limited to the orbiter or stage 1 or stage 2, radiation is often regarded as the standard treatment. When there are extra orbital sites and disease involvement, systemic therapy might be pursued alone or in combination with radiation.

Historically, radiation has excellent local control rates, meaning we treat this area, we see regression of lesions and that local control is durable over many years. That is based largely on retrospective studies that have been performed evaluating output patients treated with radiation. With more historic series, higher doses of radiation, we use 30-50 Gy, Gy is our unit of radiation. With that, most patients will never experience a relapse of that disease. It might come back to other places but not in orbit. Ocular side effects are very common with that high dose so subsequently, the dose has been lowered to 24 Gy. That's considered a moderate dose of radiation in general standards, leaving with that moderate dose. Patients can have lifelong dry eyes, and many will experience cataracts.

There's still some side effects with 24 Gy, so our study came out of recognition of a few things. One, those moderate doses can cause problems for patients in terms of [adverse events]. Two, many of our ophthalmologists and other oncologists outside of radiation in our communities were not referring patients when they were initially diagnosed out of concern for those [adverse events]. There have even been studies supporting that type of behavior. If patients didn't have a lot of symptoms, they were just watched and they waited. Out of recognition of those 2 things, we wanted to identify different strategies that may potentially be associated with great efficacy, but not the high ocular morbidity risk.

What were the methods and design of this study?

It was a phase 2, single arm, prospective study and we did something called ultra-low dose response-adapted therapy. In the radiation community, there is recognition that 4 Gy in 2 fractions, which is a low dose of radiation of just 2 treatments, can result in great outcomes for about 70% of patients. This was seen in the FORT trial (NCT00310167) where they compared 24 Gy with 4 Gy for patients with mainly follicular, but also marginal zone and MALT lymphoma.

What they observed with that study was that a lot of 4 Gy did have respectable response rates. The primary outcome of that study was local progression, and it favored the 24 Gy arm and it remained the standard. Since 70% of patients did have a great response, what we wanted to do was identify those patients that 70% that maybe will do great with just 4 Gy alone, and reserve the 24 Gy, the full dose, for the incomplete responders. That's the premise behind the study. In its phase 2, single arm, patients received 4 gray in 2 fractions to the disease in the orbit. If they had bilateral involvement, they would receive radiation to both orbits.

Then at 3 months, we would evaluate them. If they had a complete response, they were observed and if they had stable disease or progressive disease, we wanted to recommend an additional 20 Gy. If they had a partial response or a minimal response defined as more or less than 50% decrease in the tumor volume, then we would continue to watch them in 3 month intervals. At 1-year, if they didn't have a complete response, we gave them the additional 20 Gy to complete this standard course. We're trying to pull out the responders and only give the additional 20 Gy to those that really need it.

What were the findings of the trial?

We had just over 3 years follow-up and we found that 90% of patients had a complete response to the entire response adopted program, and that included 45 patients total. Forty-four of them only need 4 Gy, only 1 of them received 20 Gy to have a complete response, so that's 90% of the population. We did recommend the 20 Gy to a total of 6 patients, and 2 of them received it. Four of them elected not to have the radiation out of patient or physician preference, which is interesting. They continued to be observed or had systemic therapy. Basically, the control rates among those 45 patients that had a complete response was excellent. None of them had experienced any local relapses in orbit.

Similarly, we had a separate series of 55 patients that we treated the same way, but they were treated off protocol. Among those patients, 98% of them had a complete response to response-adapted therapy with only 2 of them requiring an additional 20 Gy to have a complete response. We have a combined cohort of 105 patients and the vast majority of them responded completely to 4 Gy and a small fraction were eligible for the additional 20 Gy. We are excited that the toxicity was collected prospectively. We only had a handful of cases of dry eye syndrome that represented about 6% of the study population. Toxicity was limited and efficacy was encouraging.

How do you think these results will influence the future of this space?

It's already made a big impact. For our patients with marginal zone lymphoma, this is our standard approach, even for the stage I and stage II patients. There are some concerns that we had initially like, you have a disease, you're taking a potentially curable patient population and giving them what's known to be a substandard dose of radiation, are you worried about higher relapse rates? We looked at a subset of patients that were newly-diagnosed, 22 patients that were treated and had stage I disease, and their local control at 2 years was 91%. We did have 3 distant failures in the contralateral orbit in the mediastinum, but the distant relapse rates were on par with what's seen in older studies that treated patients with higher doses. For us, this has already changed our practice for patients with marginal zone lymphoma. This is also because marginal zone lymphoma is very rarely life threatening.

Follicular lymphoma can be a bit more challenging, requiring more treatments over many years, and in some patients, they can succumb to the disease or to the toxicity from their treatments. I think there is some hesitancy to embrace this for stage I follicular lymphoma patients, but there's a clinical trial that's going to be opening soon that is adopting our response-adapted approach and they're gonna test it in a randomized way. This randomized trial is going to compare our response-adaptive strategy to upfront 24 Gy for patients with limited-stage follicular and marginal zone lymphoma. For patients with stage I follicular lymphoma, I think that the new data that we'll receive from the randomized trial will be helpful, but for us, we're doing this for all of our patients with stage I lymphoma.

Are there any challenges that you are facing with this or anything that might influence this research in the future?

It has a lot to do with how we discuss this treatment option with our patients. It can be anxiety provoking thinking about disease persisting while you're waiting for follow-up. I think the data that we have so far in over 100 patients is really encouraging. That can be something that we can use to encourage patients. It's important for colleges to have that discussion upfront, that this is a slow growing process, this has probably been here in your eye for many months, sometimes years before it was diagnosed. Waiting 3 months to see how you respond, we would not expect to compromise outcomes. If you have patients that you know are not going to follow-up, don't want to follow-up or have a great deal of anxiety behind it, discussing the standard dose is definitely not unreasonable. I think it's really important how we discuss it and our attitudes towards it. Our patients look to us for our opinions, so I think it's important to have those discussions early about the importance of the follow-up and the fact that we don't anticipate losing any efficacy with the delay that comes with awaiting response

assessment.

Fr community oncologists who want to learn more about this, what are the key takeaways?

The key takeaway is that this is a paradigm shift, but there is a lot of data before our study to show that 4 Gy in 2 fractions did contribute to excellent responses. There are many retrospective series people can look at to just see the outcome of 4 Gy in 2 fractions in the orbit. While this is a little bit different of an approach, overall, we do have a lot of data endorsing and supporting the high response rates of just 2 fractions. For people that will say, I don't have the published data yet to recommend doing this in my practice, I would say that there is enough data out there to endorse shifting to this approach.

This approach provides great efficacy, low toxicity, and also offers decreased cost for the patients. The financial burden decreases. Patients that have disease outside of the orbit that are going to receive chemotherapy or other systemic therapies can get this and then quickly transition to those treatments. This provides a great opportunity, not only for patients with limited stage disease, but also for those with advanced stage disease.

_REFERENCE:

_{Pinnix CC, Dabaja B, Gunther JR, et al. 3 response adapted ultra low dose radiation therapy for the definitive management of orbital indolent B-cell lymphoma. Presented at ASTRO 2022 Annual Meeting; October 23-26, 2022; San Antonio, TX.}