Radiation Therapy for Patients With R/R Non-Hodgkin Lymphoma With Incomplete Response to CAR T-Cell Therapy

Kiran Kumar, MD, MBA, UT Southwestern Medical Center, Dallas, Texas, makes the case for re-priming radiation therapy among patients with relapsed/refractory (R/R) non-Hodgkin lymphoma, including patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), who experienced incomplete response after CD19-directed chimeric antigen receptor (CAR) T-cell therapy.  

Transcript:

Hi, everyone. My name's Kiran Kumar. I'm an assistant professor of radiation oncology at UT Southwestern Medical Center in Dallas. I'll be talking about our phase 1 trial on re-priming radiation therapy for relapse refractory non-Hodgkin lymphoma patients in incomplete response after CAR T-cell therapy.

As a little background for the study, of patients with relapsed/refractory non-Hodgkin lymphoma treated with CD19-directed CAR T, only about 40% of them will achieve a complete response by day 30 [positron emission tomography] (PET)/[computerized tomography] (CT) [scan]. Of those who do not achieve a complete response, the large majority, or 70%, will ultimately fail. 

We designed this trial to help target that population that most likely will fail CAR T to see if re-priming the CAR T[-cell therapy] with radiation could help improve outcomes. This is based on preclinical and early clinical studies that suggest that there could be possible synergy and immune augmentation when combining radiation with CAR T.

Our study [used] radiation therapy after CAR T, and specifically after day 30 post-CAR T PET/CT [scan] in patients who did not have a complete response. Our hypothesis is that by the next PET/CT [scan] on day 90, we could improve the conversion to complete response from 29%, which is the historical control, to 58%. What we are presenting is the phase 1 component of this prospective single institution phase 1/2 clinical trial.

For a little more details about the patients who were included in the study, as we mentioned, these are mostly diffuse large B-cell lymphomas or relapse refractory high-grade non-Hodgkin lymphomas treated with CD19 directed CAR T. All of these patients had an incomplete response in the day 30 PET, so that's a Lugano [score of] 4 or 5.

The phase 1 component of the trial used a “Rolling 6” design with 6 patients enrolled at the definitive dose. This is the higher radiation dose that we defined as 40 to 50 gray EQD2.

Then, if there were excessive toxicities, we had a dose de-escalation down to a palliative dose that we defined as 20 to 32.5 gray EQD2. The actual cumulative dose and fractionation were up to the physician. However, we recommended hypo-fractionated regimens like 5 fractions directed only to the residual [fluorodeoxyglucose] (FDG) avid disease to minimize lymphopenia and potentially result in a more favorable immune microenvironment. 

The primary endpoint for phase 1 is just toxicity. Phase 2 is looking at response rates on day 90 PET/CT [scan]. For toxicity, we said if there was greater than 2 out of the 6 enrolled patients who had dose-limiting toxicities, then we would de-escalate. We define the dose-limiting toxicity as within 60 days of radiation by [Common Terminology Criteria for Adverse Events] (CTCAE) version 5.0, grade 4 or higher hem[atology], [and] grade 3 or higher dermatitis, pneumonitis, enteritis, or other. We also had dose-limiting toxicity as grade 3 or higher cytokine release syndrome or grade 3 or higher neurotoxicity.

We had 6 patients in the study who were enrolled from April of 2021 to July of 2022. All 6 of these [patients] had diffuse large B-cell lymphoma. 2 of the 6 had primary refractory while the other 4 had a median of 2 and a half lines of treatment prior to CAR T. 5 out of 6 patients were treated with 30 gray and 5 fractions, so 6 Gray per fraction and a hypo-fractionated method. 1 patient was treated [with] 36 gray and 10 fractions, and a lower dose per fraction was safer in that area. The toxicities were all minimal. There was 1 [case of] alopecia, 1 [case of] pneumonitis, 1 [case of] nausea [and] vomiting, and a grade 2 skin infection. All of these toxicities were grade 1 or grade 2. There were no grade 3 or higher toxicities noted. The sites that were treated were in the abdomen for 29%, in the groin for 29%, in the extremity for 29%, and then other for 1 patient.

The conclusion of the phase 1 study was that early salvage focal definitive dose radiation to sites of incomplete response on day 30 post-CAR T, PET/CT for diffuse large B-cell lymphoma patients was safe, and no de-escalation of doses [was] needed. This is a dose that's currently being used in the subsequent phase 2 component of the trial, which is ongoing, to test the efficacy. But, for now, the impact of this is that it does appear to be safe to do radiation after day 30 PET/CT [scan] and to use definitive doses in a hypo-fractionated manner.

Source: 

Kumar KA, Ravella R, Ramakrishnan Geethakumari P, et al. Phase I trial of ‘re-priming’ radiation therapy for relapsed/refractory non-Hodgkin lymphoma patients in incomplete response after chimeric antigen receptor t-cell (CAR-T) therapy. Int Journal of Radiation Oncol. Published online: October 1, 2023. doi:10.1016/j.ijrobp.2023.06.334