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

News
Article
OncologyONCOLOGY Vol 36, Issue 12
Volume 36
Issue 12
Pages: 722-723

Bradford S. Hoppe, MD, MPH, and Omran Saifi, MD, offer a peer perspective on research by Gavin Jones, MD, and colleagues into radiation therapy in diffuse large B-cell lymphoma.

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

REFERENCES

  1. Lamy T, Damaj G, Soubeyran P, et al; LYSA Group. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018;131(2):174-181. doi:10.1182/blood-2017-07-793984
  2. Poeschel V, Held G, Ziepert M, et al; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019;394(10216):2271-2281. doi:10.1016/S0140-6736(19)33008-9
  3. Shi Z, Das S, Okwan-Duodu D, et al. Patterns of failure in advanced stage diffuse large B-cell lymphoma patients after complete response to R-CHOP immunochemotherapy and the emerging role of consolidative radiation therapy. Int J Radiat Oncol Biol Phys. 2013;86(3):569-577. doi:10.1016/j.ijrobp.2013.02.007
  4. Phan J, Mazloom A, Medeiros LJ, et al. Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol. 2010;28(27):4170-4176. doi:10.1200/JCO.2009.27.3441
  5. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol. 2004;22(15):3032-3038. doi:10.1200/JCO.2004.06.088
  6. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med. 1998;339(1):21-26. doi:10.1056/NEJM199807023390104
  7. Held G, Murawski N, Ziepert M, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32(11):1112-1118. doi:10.1200/JCO.2013.51.4505
  8. Pfreundschuh M, Murawski N, Ziepert M, et al. Radiotherapy (RT) to bulky (B) and extralymphatic (E) disease in combination with 6xR-CHOP-14 or R-CHOP-21 in young good-prognosis DLBCL patients: results of the 2x2 randomized UNFOLDER trial of the DSHNHL/GLA. J Clin Oncol. 2018;36(15_suppl):7574-7574. doi:10.1200/JCO.2013.51.4505
  9. Held G, Zeynalova S, Murawski N, et al. Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement. J Clin Oncol. 2013;31(32):4115-4122. doi:10.1200/JCO.2012.48.0467
  10. Persky DO, Li H, Stephens DM, et al. Positron emission tomography-directed therapy for patients with limited-stage diffuse large B-cell lymphoma: results of Intergroup National Clinical Trials Network study S1001. J Clin Oncol. 2020;38(26):3003-3011. doi:10.1200/JCO.20.00999
  11. Hoppe BS, Moskowitz CH, Filippa DA, et al. Involved-field radiotherapy before high-dose therapy and autologous stem-cell rescue in diffuse large-cell lymphoma: long-term disease control and toxicity. J Clin Oncol. 2008;26(11):1858-1864. doi:10.1200/JCO.2007.15.4773
  12. Saifi O, Breen W, Lester SC, et al. The impact of radiation timing in peri-CAR T-cell therapy on local control for relapsed/refractory B-cell non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys.2022;114(3 Suppl):S85-S86. doi:10.1016/j.ijrobp.2022.07.492
  13. Saifi O, Breen WG, Lester SC, et al. Does bridging radiation therapy affect the pattern of failure after CAR T-cell therapy in non-Hodgkin lymphoma? Radiother Oncol. 2022;166:171-179. doi:10.1016/j.radonc.2021.11.031
  14. Saifi O, Breen W, Lester S, et al. In-field recurrences in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) bridged with radiation prior to CD19 chimeric antigen receptor T-cell therapy (CART). J Clin Oncol. 2022;40(16 Suppl):abstr 7556. doi:10.1200/JCO.2022.40.16_suppl.7556
  15. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447
  16. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0
  17. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980
  18. Sim AJ, Figura NB, Dohm AE, et al. In-field failures in patients undergoing bridging radiotherapy for CD19-directed chimeric antigen receptor (CAR) T-cell therapy for recurrent/refractory large B-cell lymphomas. Int J Radiat Oncol Biol Phys. 2021;111(3 Suppl):S131. doi:10.1016/j.ijrobp.2021.07.297
  19. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373-377. doi:10.1038/nature14292
  20. DeSelm C, Palomba ML, Yahalom J, et al. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther. 2018;26(11):2542-2552. doi:10.1016/j.ymthe.2018.09.008
  21. Ladbury C, Kambhampati S, Othman T, et al. Role of salvage radiation treatment of relapses in relapsed/refractory diffuse large B cell lymphoma post-autologous stem cell transplant. Int J Radiat Oncol Biol Phys. 2022;113(3):594-601. doi:10.1016/j.ijrobp.2022.02.015
  22. Saifi O, Breen W, Lester SC, et al. Comprehensive salvage radiotherapy for limited relapsed B-cell non-Hodgkin lymphoma following CD19 chimeric antigen receptor T-cell therapy. Int J Radiat Oncol Biol Phys. 2022;114(3 Suppl):S56. doi:10.1016/j.ijrobp.2022.07.436
  23. Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol. 2011;100(1):86-92. doi:10.1016/j.radonc.2011.05.013
  24. Yahalom J, Illidge T, Specht L, et al; International Lymphoma Radiation Oncology Group. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2015;92(1):11-31. doi:10.1016/j.ijrobp.2015.01.009
  25. Tseng YD, Cutter DJ, Plastaras JP, et al. Evidence-based review on the use of proton therapy in lymphoma from the Particle Therapy Cooperative Group (PTCOG) Lymphoma Subcommittee. Int J Radiat Oncol Biol Phys. 2017;99(4):825-842. doi:10.1016/j.ijrobp.2017.05.004
  26. Patel CG, Peterson J, Aznar M, et al. Systematic review for deep inspiration breath hold in proton therapy for mediastinal lymphoma: a PTCOG Lymphoma Subcommittee report and recommendations. Radiother Oncol. Published online October 14, 2022. doi:10.1016/j.radonc.2022.10.003
  27. Baron JA, Wright CM, Maxwell R, et al. Proton radiotherapy following chemotherapy in the management of aggressive mediastinal non-Hodgkin lymphomas: a PTCOG Lymphoma Subcommittee collaboration. Adv Radiat Oncol. Published online October 3, 2022. doi:10.1016/j.adro.2022.101090
  28. Tseng YD, Hoppe BS, Dedeckova K, et al. Risk of pneumonitis and outcomes after mediastinal proton therapy for relapsed/refractory lymphoma: a PTCOG and PCG collaboration. Int J Radiat Oncol Biol Phys. 2021;109(1):220-230. doi:10.1016/j.ijrobp.2020.08.055
  29. Yanagi I, Okuda H, Fujii S. Further studies on the mechanism of in vitro stimulation of lipolysis by adrenaline. J Biochem. 1968;63(2):249-253. doi:10.1093/oxfordjournals.jbchem.a128767
Related Videos
Some patients with large B-cell lymphoma may have to travel a great distance for an initial evaluation for CAR T-cell therapy.
Education is essential to referring oncologists manage toxicities associated with CAR T-cell therapy for patients with large B-cell lymphoma.
There is no absolute age cutoff where CAR T cells are contraindicated for those with large B-cell lymphoma, says David L. Porter, MD.
David L. Porter, MD, emphasizes referring patients with large B-cell lymphoma early for CAR T-cell therapy consultation.
It may be applicable to administer CAR T-cell therapy to patients with large B-cell lymphoma in a community or outpatient setting.