Radiation Therapy in Diffuse Large B-Cell Lymphoma: A Little Boost Gets You Over the Finish Line

Recent advancements in systemic therapies for diffuse large B-cell lymphoma (DLBCL) have revolutionized outcomes and prognosis. Chemotherapy, conjugate antibody systemic therapy, transplant therapy, and chimeric antigen receptor (CAR) T-cell therapy are currently the dominant therapeutic options for DLBCL. Radiation therapy (RT), historically the key treatment for DLBCL, has been swept aside in favor of systemic therapies that are presumed less toxic and more efficacious.

Despite the excellent outcomes with the current upfront PET/CT response-based treatment in early-stage DLBCL without RT,^1,2 one must not overlook certain situations in which RT can have an important positive impact on outcomes. The predominant pattern of relapse of DLBCL following chemotherapy involves the original sites of disease, even in patients who achieve complete remission (CR).³ Conversely, the predominant pattern of relapse in patients who receive consolidative RT is outside the field of RT.⁴ Such predictable patterns of relapse emphasize the important utility of RT to improve local control in patients with high risk of relapse. This may translate into an event-free survival benefit and eventual overall survival (OS) benefit.

Unfavorable factors associated with increased risk of relapse include bulky disease and skeletal involvement, which have been shown to benefit from consolidative RT.^5-9 Further, certain biological factors are associated with increased risk of relapse, such as activated B-cell, double-hit, and triple-hit histologies.¹⁰ While the additional benefit of RT has not been well studied in these patients, their higher risk of relapse, even among those with early-stage favorable disease,¹⁰ calls for consideration of consolidative RT. Similarly, patients whose PET/CT scan results indicate a slow early response (SER) and/or partial response (PR) to initial systemic therapy are at higher risk of relapse. RT can improve these patients’ outcomes to the point where they are comparable with those of patients who achieved CR.^7,8,10

The outcomes of DLBCL in the relapsed/refractory (R/R) setting are poor. This calls for treatment escalation to help improve outcomes. RT plays an important role in the peritransplant11 and peri–CAR T-cell settings.¹² As the authors mentioned, RT improves outcomes when offered as part of the peri–autologous stem cell transplant (ASCT) regimen. The benefit may be most evident in patients who have bulky or limited sites of disease, or those with a pre-ASCT PR. Similarly, RT is promising as a bridge to CAR T-cell, with a favorable impact beyond palliating symptomatic sites and improving rates of CAR T-cell infusion. Recent work has shown the predominant pattern of relapse following CAR-T in unirradiated patients to involve preexisting sites of disease.¹³ This highlights the possibility of using RT to augment local control and durable response rates in patients who present with limited disease prior to CAR T-cell infusion. Patients with limited disease who received comprehensive bridging RT had a trend to better progression-free survival compared with those who did not receive RT.¹³ The 1-year local control rate of disease sites bridged with RT is greater than 80%.^12-14 This is impressive when compared with the CAR T-cell therapy historical 1-year durable response rate of about 50%.^15-17 We agree with the authors that patients who present with limited disease prior to CAR T-cell therapy should be treated comprehensively to definitive RT doses. There are no clear data or guidelines on the recommended dose of bridging RT. One might consider escalating the dose in the presence of high-risk features that can predict in-field local failure, which include, but are not limited to, bulky tumor size, Myc/BCL rearrangements,¹⁴ and high tumor metabolic volume.¹⁸

The combination of a narrow bridging time window and late referrals to radiation oncology constitutes a major challenge for definitive bridging RT attempts. At our institution, we have addressed this challenge with accelerated treatment using twice-daily radiation treatment and early referrals to radiation oncology whenever possible. For patients who present with diffuse disease prior to CAR T-cell therapy, palliative low-dose RT may be sufficient to control both symptoms and disease. R/R DLBCL is radiosensitive, and low-dose RT is sufficient to reprime the immune system and sensitize the lymphoma cells to CAR T-cell therapy.^19,20

Despite all the first- and second-line treatment efforts, a significant number of DLBCL patients relapse. At that point, multiple other systemic treatment options can be offered, and RT can provide palliative treatment. However, a subset of patients might still benefit from curative RT. For instance, patients with 1 site of relapse following ASCT had improved OS when treated with salvage RT compared with salvage chemotherapy.²¹ This might also apply to patients with limited relapsed disease, post CAR T-cell therapy; recent data show a survival benefit with comprehensive salvage RT.²²

RT toxicity was a major concern when it was delivered as a systemic therapy—eg, total body irradiation, total lymphatic irradiation, or subtotal lymphatic irradiation. Doses prescribed to these large fields were sometimes up to 40 to 50 Gy. However, modern RT utilizes lower doses.²³ It is more targeted and utilizes contemporary fields²⁴ and techniques, which leads to reduced doses to the organs at risk, minimizing the acute and late-RT toxicity. The International Lymphoma Radiation Oncology Group has developed expert consensus for treating extranodal and nodal NHL using involved-site radiotherapy (ISRT). These fields are much smaller and more personalized to the patient’s initial sites of involvement compared with the previously used involved-field radiotherapy. Toxicity can be further lowered by using newer techniques available, including intensity-modulated radiotherapy and proton therapy for disease located in critical locations such as the mediastinum.^25,26 While data on late effects with contemporary techniques are immature, early data have demonstrated that they are safe and effective.^27-29

In summary, selected patients with DLBCL have excellent outcomes without RT. However, ISRT in the upfront or R/R setting may prolong remission and avoid subsequent toxic therapeutic approaches when offered to the right subset of patients, who include those with unfavorable characteristics and/or predictable site of relapse (ie, limited disease, bulky disease, SER/PR).

AUTHOR AFFILIATIONS:
Bradford S. Hoppe, MD, MPH¹; and Omran Saifi, MD¹

¹Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL

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