The integration of radiation therapy into chimeric antigen receptor (CAR) T-cell therapy may improve outcomes for patients with relapsed or refractory lymphoma, according to Charles A. Enke, MD, Professor and the Bill Bures and Jerry Pabst Chair in Radiation Oncology at the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha. Dr. Enke described this approach at the 2021 Pan Pacific Lymphoma Conference, which was sponsored by his institution.1
Charles A. Enke, MD
With second-generation CAR T-cell constructs, such as axicabtagene ciloleucel and tisagenlecleucel, durable complete responses can be achieved in about 40% of heavily pretreated patients, with some 50% of patients still alive at 2 years. Based on plateaus of the Kaplan-Meier curves, most recurrences and cases of disease progression occur within the first 6 months, and data are emerging that may suggest who those unfortunate patients are most likely to be, Dr. Enke noted.
Predictors of Local Failure
Radiotherapy may have a role to play in ameliorating the potential for local failure. A recent study from Moffitt Cancer Center and Research Institute examined the patterns and predictors of local failure in patients with recurrent or refractory large B-cell lymphomas following CAR T-cell therapy.2 Researchers examined 469 individual positron-emission tomography (PET)-detected lesions in 63 patients. PET/computed tomography (CT) images were analyzed before and after treatment to assess the progression of existing lesions (local failures) vs new, nonoverlapping lesions (de novo failures) and to identify lesions at high risk for disease progression. (Patients with bridging radiotherapy were excluded.)
At a median follow-up of 12.6 months, 36 patients (57%) had recurrences, of whom 31 (86%) had a component of local failure. These 36 patients with disease progression had 297 lesions being observed, yielding a median of 5 lesions per patient. More than half the lesions continued to respond to CAR T-cell therapy, and 84% had at least one pretreatment lesion that remained controlled.
Patterns of failure were strictly local alone in 36% of these patients, de novo (new) in 14%, and a combination of local and de novo in 50%. “Altogether, 86% of patients had local failure as part of the failure pattern,” reported Dr. Enke.
Lesions at high risk for local failure included those with a diameter of at least 5 cm (odds ratio [OR] = 2.34; P < .001), a maximum standardized update value ≥ 10 (OR = 2.08; P < .001), or extranodal disease (OR = 1.49; P = .01). The presence of multiple lesions or necrosis was not an independent predictor. In the 69 patients eligible for survival analysis, those with any lesion ≥ 5 cm (n = 46, 67%) experienced inferior progression-free survival (hazard ratio [HR] = 2.41; P = .02) and overall survival (HR = 3.36; P = .02).
The study concluded that most patients who experience recurrence following CAR T-cell therapy do so as a component of local disease progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. “Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T-cell treatment failure. Locally directed therapies to high-risk lesions, such as radiotherapy, may be a viable strategy to prevent CAR T-cell failures,” the authors wrote.
The association between lesion size and clinical outcomes is important, Dr. Enke said. “This could predict failure patterns and outcome,” he said. “Going forward, I think we need to think about the role radiotherapy should play in the CAR T-cell–treated patients who have PET-positive lesions ≥ 5 cm or a maximum standardized update value ≥ 10. We should consider these patients for treatment.”
Additional Benefits of Radiotherapy
Dr. Enke then pointed to two additional possible roles for radiotherapy during CAR T-cell therapy, mostly during the bridging interval: for palliation of symptomatic lesions prior to giving CAR T-cell therapy and for targeted treatment of low-volume recurrences in relapsed patients, which may help gain control of aggressive disease, he said.
Research has also shown that radiotherapy given during bridging, for these reasons, may reduce the onset of cytokine-release syndrome. Other research has shown that neurotoxicity may also be reduced when radiotherapy is used as part of lymphodepletion. Dr. Enke added that experimental studies are finding the addition of low-dose radiotherapy conditioning enables CAR T cells to mitigate antigen escape (ie, render sensitivity to cells that otherwise do not express antigen).3
Radiotherapy is generally delivered after leukapheresis, to avoid difficulties in harvesting an adequate number of T cells; however, the bridging interval—which can be as short as 2 weeks or as long as 3 or 4 weeks—may be “an opportune time” to consider radiotherapy, especially when patients have predictors that CAR T-cell therapy alone may be ineffective. There is also interest in radiotherapy playing a role in lymphodepletion, as some data suggest it may be more effective than cyclophosphamide and fludarabine, noted Dr. Enke.
Timing of Radiotherapy
“The big question is whether it is possible to give meaningful doses of radiation during the bridging interval, and, for that, what is the appropriate duration?” asked Dr. Enke.
A study from Dr. Enke’s institution, the University of Nebraska, evaluated twice-daily radiotherapy given during the bridging therapy interval (unpublished data). The study treated 54 patients with relapsed or refractory diffuse large B-cell lymphoma with radiotherapy and allogeneic stem cell transplantation (ASCT). Radiotherapy was given either as 36 Gy in 20 fractions over 4 weeks after ASCT or as 36 Gy in 20 fractions over 2 weeks (treated twice daily) before ASCT. The twice-daily delivery of radiotherapy proved feasible and was associated with a “dramatic difference” in outcomes, including locoregional control, progression-free survival, and overall survival, Dr. Enke reported. “We showed we really could improve the odds of patients eligible for transplantation, and it’s possible in that time frame,” he added.
Trends in Radiotherapy for Lymphoid Malignancies: Is Less More?
The trends in radiotherapy in lymphoma are for lower doses, smaller volumes (treating the involved site and not the field), techniques to reduce doses to the organs at risk, and identification of patients for whom radiotherapy may be omitted altogether, noted Dr. Enke.
Reduced doses of intensity-modulated radiotherapy were evaluated in gastric mucosa-associated lymphoid tissue (MALT) lymphomas, in a study of 32 patients treated at MD Anderson.4 The study compared different dose levels: 30–36 Gy (usually 1.5 Gy/fraction) vs 24 Gy (usually 2 Gy/fraction). At 2 years, the rates of 2-year freedom from local treatment failure, freedom from treatment failure, and overall survival were 100%, 100%, and 97%, respectively, with no differences shown between the two dose groups.
The omission of radiotherapy altogether may be safely accomplished in patients with Hodgkin lymphoma, under some circumstances, continued Dr. Enke. This issue has been evaluated in a few large trials, including several by the German Hodgkin Study Group (GHSG) and the Italian GITIL/FIL HD0607 trial.
The German GHSG HD17 trial enrolled 1,100 patients with a complete metabolic response after two cycles of escalated etoposide, cyclophosphamide, and doxorubicin and regular doses of bleomycin, vincristine, procarbazine, and prednisone plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2).5 Patients were randomly assigned to receive standard combined-modality treatment or treatment guided by PET scans after four cycles (PET4). The 5-year progression-free survival was 97.3% and 95.1%, respectively—a difference of 2.2%.
The Italian GITIL/FIL HD0607 study enrolled 280 patients with advanced-stage Hodgkin lymphoma who presented at baseline with a large nodal mass (≥ 5 cm) in complete metabolic response after ABVD chemotherapy.6 Patients were randomly assigned prospectively to receive radiotherapy over the mass or no further treatment.
The final analysis showed that consolidation radiotherapy may be safely omitted in patients presenting with a large nodal mass and a negative scan after two and six cycles of ABVD, irrespective of the nodal mass size detected at baseline. The lack of apparent benefit for radiotherapy held true even for patients with a nodal mass ≥ 10 cm. “The size [of the residual tumor] in itself may not be that important of a predictor,” he commented.
Finally, Dr. Enke added that radiotherapy, even at low doses, may be effective in many cases, as it was for a particular patient with small lymphocytic lymphoma. He treated the patient with 2 Gy/fraction x 2, for 4 Gy total (ie, “boom boom”) without other systemic treatment. The patient responded well to what Dr. Enke viewed as “almost homeopathic radiotherapy in terms of its side-effect profile.”
Another use for this type of limited treatment is conjunctival lymphoma, where it may provide a disease control rate of up to 80% for 2 years. There are patients with low-grade indolent lymphomas who meet the criteria for standard 24 Gy x 12 treatment but who can do well with this limited approach. “The understanding is that if they experience disease progression, they can still receive definitive radiation, so you have not burned bridges,” Dr. Enke explained.
DISCLOSURE: Dr. Enke reported no conflicts of interest.
REFERENCES
1. Enke C: What’s next for radiotherapy for lymphoid malignancies? 2021 Pan Pacific Lymphoma Conference. Presented August 10, 2021.
2. Figura NB, Robinson TJ, Sim AJ, et al: Patterns and predictors of failure in recurrent or refractory large B-cell lymphomas following chimeric antigen receptor (CAR) T-cell therapy. Int J Radiat Oncol Biol Phys. July 6, 2021 (early release online).
3. DeSelm C, Palomba ML, Yahalom J, et al: Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther 26:2542-2552, 2018.
4. Pinnix CC, Gunther JR, Milgrom SA, et al: Outcomes after reduced-dose intensity modulated radiation therapy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Int J Radiat Oncol Biol Phys 104:447-455, 2019.
5. Borchmann P, Plütschow A, Kobe C, et al: PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphomas (GHSG HD17): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 22:223-234, 2021.
6. Gallamini A, Rossi A, Patti C, et al: Consolidation radiotherapy could be safely omitted in advanced Hodgkin lymphoma with large nodal mass in complete metabolic response after ABVD: Final analysis of the randomized GITIL/FIL HD0607 trial. J Clin Oncol 38:3905-3913, 2020.
