Skip to main content
NCBI home page
The British Journal of Radiology logoLink to The British Journal of Radiology
. 2021 Aug 31;94(1127):20210360. doi: 10.1259/bjr.20210360

Salvage radiotherapy for primary refractory and relapsed diffuse large B-Cell lymphoma

Eric D Brooks 1, Penny Fang 2, Chelsea C Pinnix 2,✉
PMCID: PMC8553185  PMID: 34378402

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, accounting for 30–40% of all non-Hodgkin lymphoma cases and presenting later in life, most often in the sixth decade. Although DLBCL is curable, long-term remission rates are only 60–80%. The most recent major advance in upfront therapy for DLBCL was the monoclonal anti-CD20 antibody rituximab, which was approved in the late 1990s; now, 25 years later, up to 40% of patients will experience primary refractory or relapsed disease, thereby underscoring the importance of salvage therapy. Radiation therapy can be highly effective in DLBCL, both initially as consolidation therapy and later as salvage therapy and is currently being explored in the context of immune and cellular therapies. The aim of this review is to examine the therapeutic approaches for relapsed or refractory DLBCL, with a focus on whether using radiation therapy as salvage therapy can improve the likelihood of cure.

Background and current first-line treatment approaches for DLBCL

Diffuse large B-cell lymphoma (DLBCL) represents a wide spectrum of disease. While DLBCL is curable, long-term remissions are achieved in only 60–80% of patients.1 Increasing numbers of patient- and disease-related clinical factors are recognized as affecting the probability of cure.2–5 These factors include the revised International Prognostic Index (IPI) score,6 the presence of bulky tumor (e.g. >7.5 cm in diameter),7,8 and the molecular and biological subtype (e.g. germinal center B-cell-like [GCB] vs non-GCB; MYC, BCL2, BCL6 translocations or expression).9,10 Approximately, 40% of patients will experience primary refractory or relapsed disease.2,11

Although DLBCL is heterogeneous across both early (stage I-II) and advanced (stage III-IV) disease, the hallmark of therapy is similar, consisting of doxorubicin-based immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), followed by radiation therapy (RT) for eligible patients who experience a response to that therapy.12 However, whether RT should be used as upfront consolidative therapy in either early or advanced disease remains controversial.12–28 Patients with limited-stage disease may be offered consolidative RT after a complete response to systemic therapy in lieu of additional cycles of chemotherapy, especially in cases of bulky disease or osseous involvement. The goal of therapy is to achieve complete response, and maintain it, with the least amount of toxicity possible.

The use of positron emission tomography–computed tomography (PET-CT) is being explored in clinical trials in attempts to identify patients with untreated early-stage DLCBL who may achieve a durable remission with fewer cycles of cytotoxic chemotherapy without consolidative RT.13,29,30 Because both RT and the chemotherapy agents used in the R-CHOP regimen can have long-lasting cardiac and myelosuppressive effects in addition to increasing the risk of secondary malignancies, minimizing adverse effects whenever possible in the initial treatment of DLBCL is paramount. The decision to reduce the numbers of cycles of chemotherapy or omit RT from the initial treatment regimen should be made on an individual basis, as either modality can have greater or lesser toxicity depending on baseline factors, including disease distribution. Also, use of contemporary RT approaches for patients with lymphoma can minimize RT-related toxicity via reducing the radiation dose to surrounding normal tissues.31,32

Aside from the need to minimize the toxicity of first-line treatment, attempts to improve the likelihood of response to first-line treatment have had limited success since the advent of rituximab more than two decades ago.2,7 As noted earlier, up to 40% of patients with DLBCL will have either primary refractory (15%) or relapsed (25%) disease.2,11 In the upfront setting, the use of more intensive regimens such as dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) may not improve outcomes over those after standard R-CHOP therapy,33,34 and how best to treat disease that has relapsed or progressed after first-line therapy remains an open question at this time.

Salvage strategies

Relapsed disease

The need for effective salvage or second-line treatment for DLCBL has been acknowledged for several decades. The first trial to compare autologous stem cell transplant (ASCT) vs conventional chemotherapy for non-Hodgkin lymphoma that had relapsed after initial doxorubicin-based chemotherapy was the PARMA trial.35 In that trial, patients who had had a response to two courses of conventional chemotherapy with DHAP (dexamethasone, cytarabine and cisplatin) were randomly assigned to receive four additional courses of DHAP (with or without RT) or RT and high-dose chemotherapy with BEAC (carmustine, etoposide, cytarabine, cyclophosphamide, and mesna) followed by ASCT.35 75 of the patients in this study (68%) had DLBCL histology, and 95 (88%) were in first relapse. The event-free survival rate was tripled in the ASCT group (46% vs  12% for DHAP), and the overall survival rate improved by an astonishing 65% (53% vs  32% for DHAP) at 5 years. This landmark study, published in 1995, suggested that salvage therapy followed by high-dose chemotherapy and ASCT should be considered the standard of care for eligible patients with relapsed DLBCL.

Several lessons were learned from the PARMA study. First, only two-thirds of patients with relapsed disease (64%) responded to a second line of chemotherapy with DHAP, highlighting the aggressive nature of relapsed disease and suggesting that better systemic regimens, or other treatment modalities, were needed for salvage therapy. Indeed, in the subgroup of patients with disease that did not respond to second-line DHAP, only 21% experienced a response to a third-line regimen, reinforcing the concept that resistant disease likely requires alternative treatment modalities for eradication. Notably, ASCT, although offering potentially exciting results, was not a viable treatment strategy for all patients with relapsed or refractory disease. Indeed, ASCT was used only for patients with disease that was chemosensitive to second-line DHAP (50%), and only half of those patients with chemosensitive disease were healthy enough to undergo ASCT. Moreover, the mortality rate in the ASCT group was high at 6%, and the associated morbidities (e.g. infection, cytopenia, and others) effectively precluded the use of ASCT for frail patients.35 In short, the limitations of high-dose chemotherapy and ASCT correspond to a 25% chance that a patient with relapsed disease will be eligible for ASCT—or conversely, that 3 of 4 patients with relapsed disease will require salvage with other types of therapy.

The subsequent Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial evaluated the potential benefit of adding rituximab to salvage therapy and compared two platinum-based regimens, R-DHAP vs R-ICE (rituximab, ifosfamide, carboplatinum and etoposide).36 In that trial, 396 patients with primary refractory or first-relapse DLBCL were randomized to receive R-ICE or R-DHAP, followed by BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT for eligible patients. The two chemotherapy regimens were equally effective at 3 years of follow-up (37% progression-free survival and 49% overall survival for both R-ICE and R-DHAP). Not surprisingly, patients who received ASCT had a better progression-free survival rate, at about 53% at 3 years for both regimens.

Other lessons from this study included the recognition that the prognosis for disease that relapses within 1 year after initial treatment is abysmal. Moreover, the CORAL trial showed that only 50% of patients were eligible for ASCT owing to poor response or not being healthy enough to tolerate treatment, which echoes the 50% transplant-eligibility rate in PARMA.35 Another important observation was that relapse or progression at study entry most often appeared at the initial site(s) of disease. The notion of local relapse is important, in that it suggests that patients may benefit from RT that is locally directed to areas of resistant disease. Indeed, investigators from Memorial Sloan Kettering Cancer Center noted that patients who had persistent disease before transplant had a 60% rate of disease relapse compared with 26% for patients who had received RT before ASCT.37

Collectively, these two landmark studies helped to establish the success rates for salvage chemotherapy in the modern era, demonstrated the value of ASCT, and hinted at which patients may benefit from the inclusion of RT in salvage therapy for relapse (Figure 1; suggested guide in considering salvage for relapsed disease). A subsequent single-institution review from investigators at the University of Rochester considered patterns of relapse among 100 patients who had undergone ASCT for relapsed DLBCL.38 Disease relapsed at the initial sites in 40–75% of patients regardless of the type of initial treatment, echoing the finding from the CORAL trial that relapse at the initial site was common. Moreover, in approximately 70% of patients with relapse at initial sites, that relapse was an isolated incident, and this was more common among patients with advanced (stage III/IV) disease (56%) than among patients with early (stage I/II) disease (27%). These findings suggest that among patients with relapsed DLBCL who undergo intensive systemic therapy with ASCT, local recurrence remains a significant threat to long-term disease control.

Figure 1.

Figure 1.

Open in a new tab

Proposed algorithm for radiation therapy considerations in the relapsed setting. ASCT, autologous stem cell transplant; CR, complete response; RT, radiation therapy.

RT in lieu of systemic therapy for patients with partial response to front-line therapy?

Several recent trials of patients with early-stage DLBCL in whom response was adapted according to findings from PET-CT scans indicate that RT may have a role in salvage therapy for patients with response to frontline therapy but with residual PET-positive DLBCL. In the LYSA study, 300 patients with early-limited stage DLBCL were randomized to receive 4–6 cycles of R-CHOP (based on baseline risk factors), with or without consolidative RT for patients who experienced a complete response.13 Although the study question focused on the effects of omitting RT, the outcomes of patients with a partial response to four cycles of R-CHOP offer insight to a potentially valuable approach for such patients. Patients with positive findings on PET-CT (defined visually as a score of 3 or more on the 5-point scale [5-PS]) after four cycles were recommended to receive an additional two cycles of R-CHOP and 40 Gy of involved-field RT (IFRT).

Overall, nearly all (88%) of the patients in the LYSA trial achieved a complete response, a testament to the success of R-CHOP in the modern era. However, 12% of patients (n = 38) had a partial response to therapy. Of those 38 patients, most (71%) received the intended additional two cycles of R-CHOP followed by RT. Patients with a partial response after four cycles of R-CHOP who received an additional two cycles of R-CHOP alone (29%) or, as was intended, with RT (71%), had no difference in event-free survival at 5 years and only a 5–7% numerical EFS difference relative to patients who achieved a complete response upfront (85%–90%). Moreover, no patient who received RT for a partial response experienced local relapse. These highly encouraging findings, that patients with a partial response who received additional systemic therapy followed by RT had outcomes rivaling those for patients with a complete response, suggest that RT may be useful for providing durable disease responses in the absence of aggressive salvage systemic therapies (Figure 2).

Figure 2.

Figure 2.

Open in a new tab

A-B. In Figure 2A, a 77-year-old female with GCB DLBCL and a bulky mesenteric mass underwent R-CHOP x 6 (Panel A). She had a significant response but still had persistent 5-PS of 5 in the residual area of tumor bulk (Panel B). She underwent salvage radiotherapy alone for this persistent area of PET positivity given its small volume. In contrast, in Figure 2C-D, a 59-year-old female with non-GCB DLBCL of the right upper lobe of the lung and hilum was treated with R-CVP (Panel C). She had only a modest response and still had persistent 5-PS of 5 (Panel D). Given the relatively considerable amount of residual PET avid disease, she was not considered for salvage with radiotherapy alone. Instead, she was treated with salvage R-ICE considering her substantial primary refractory disease. This figure helps to highlight, and offer examples, of when patients with primary refractory disease may, or may not, be considered for salvage radiotherapy alone in the setting of 4-5-PS PET-avid disease after frontline immunochemotherapy. ASCT, autologous stem cell transplant; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell-like; PET, positron emission tomography; 5-PS, 5 point scale.

These encouraging results after salvage RT for patients with limited-stage DLBCL and a partial response to front-line therapy were further substantiated in a recent National Clinical Trials Network Phase II study, S1001.39 In that trial, 132 patents with non-bulky early-stage DLBCL were enrolled and planned for three cycles of R-CHOP followed by interim PET-CT. Patients with a negative PET scan at that time were to be given one additional cycle of R-CHOP, and those with a positive interim PET-CT scan (a score or 4–5 on the 5-PS) were to receive RT to 45 Gy with IFRT (36 Gy to the initial site of disease followed by a 9 Gy boost to areas of fluorodeoxyglucose avidity). After IFRT, these patients were given ibritumomab (an anti-CD20 monoclonal antibody linked to the radioactive isotype yttrium-90). Of 132 eligible patients, 128 had central review of the interim PET-CT scan. PET positivity that was not due to infection was documented in 14 patients (11%), similar to the 12% of patients who experienced partial response after four cycles of R-CHOP in the LYSA study. Salvage therapy with IFRT and ibritumomab resulted in a 67% complete response rate. At a median follow-up time of roughly 5 years, only six patients developed progressive disease after therapy, and all six had not received RT (four patients with interim PET-negative scans treated with four cycles of R-CHOP, one patient with an interim PET-positive scan who declined RT, and one patient who had suspended treatment after one cycle of R-CHOP). Of particular note, the S1001 study reported that no patient who had received RT had experienced relapse at the time of publication, despite having had a positive interim PET-CT scan. Overall, patients with interim PET-negative scans and patients with interim PET-positive scans had similar outcomes at 5 years when RT and a radionucleide pharmaceutical were given as the only form of salvage therapy (progression-free survival rates of 89% for PET-negative vs 86% for PET-positive).

Another large randomized study, the FLYER trial, assigned 592 patients aged 18–60 years with non-bulky (<7.5 cm) stage I-II DLBCL to receive six cycles of R-CHOP or four cycles of R-CHOP followed by two doses of rituximab without RT (except for patients with testicular lymphoma).30 This international, multicenter non-inferiority Phase III trial showed that four cycles of R-CHOP plus two doses of rituximab was not inferior to six cycles of R-CHOP. The trial accrual period spanned a decade (2005–2016), and therefore the response assessment criteria were not uniformly based on PET-CT findings.29 30 patients had either a partial response (n = 8) or an unclassified response (n = 22) after front-line therapy. Of the eight patients with a partial response after six cycles of R-CHOP (n = 5) or four cycles of R-CHOP +2 of rituximab (n = 3), RT alone was given to five patients with no evidence of progression after therapy. Despite the small numbers of patients, these findings, coupled with the outcomes after RT for patients with partial response on the LYSA and S1001 trials, suggest that RT may compensate for the presence of residual DLBCL for those with a partial response after initial therapy with R-CHOP.

This strategy of PET-CT-directed RT has emerged for patients with advanced DLBCL as well.40 In one study in British Columbia, patients with advanced DLBCL were given six–eight cycles of R-CHOP, and RT was offered to patients with a positive end-of-treatment PET-CT scan (defined as a score of 4–5 on the 5-PS). Outcomes for patients with PET-positive disease that did not progress and who received RT had outcomes rivaling those of patients with PET-CT-negative scans (3 year time to progression rates of 76% vs 83%, p = 0.3).

In the absence of randomized data on the use of RT alone to salvage PET-persistent disease, these reports offer insight into how DLBCL that partially responds to front-line therapy could be managed. The existing data suggest that RT alone may be sufficient in some cases regardless of disease stage at presentation. However, selection bias and other limitations inherent in any retrospective or unplanned subgroup analysis mean that clearly defining which patients would benefit from this strategy remains an area of ongoing interest. Systemic salvage therapies remain the cornerstone of treatment for patients with DLBCL refractory to frontline immunochemotherapy, however these studies highlight a potential role for RT in a selected patient population. (Figure 3; proposed algorithm for salvage considerations in the setting of persistent FGD avid disease after frontline immunochemotherapy).

Figure 3.

Figure 3.

Open in a new tab

Proposed algorithm for radiation therapy considerations for persistent FDG avid abnormalities after frontline immunochemotherapy. ASCT, autologous stem cell transplant; CR, complete response; FDG, fluorodeoxyglucose; PR, partial response; RT, radiation therapy.

The decision on treatment volume, dose, and timing of RT around transplant and systemic therapy is beyond the scope of this report but has been discussed in detail elsewhere.41 A radiation dose of 30 Gy is recommended as consolidation for patients with a complete response to systemic therapy based on PET-CT, however lower consolidative doses may be comparable.42 On the other hand, sites of persistent PET-CT-positive disease (i.e. a 5-PS score of 4–5 or biopsy-confirmed) should be considered for higher RT doses, i.e. 40–50 Gy.43 The treatment volume and margins used will also rely heavily on the location and extent of the disease that is to be treated as well as the radiation treatment approach utilized.41

Emerging therapies for primary refractory DLBCL

The ongoing need for effective therapies for primary refractory DLBCL has also been illustrated by the results of several retrospective or observational studies. For example, the multicohort, international retrospective SCHOLAR-1 pooled analysis confirmed the poor outcomes associated with refractory DLBCL (defined as progressive or stable disease being the best response during systemic therapy [>4 cycles of front-line therapy or 2 cycles of later-line therapy]) or relapsed disease appearing within 12 months after ASCT.44 Among 636 patients who met the definition of refractory disease in two Phase III trials (the CORAL trial and the Canadian Cancer Trials Group LY.12 trial) and two observational studies (MD Anderson Cancer Center and the University of Iowa/Mayo Clinic), the objective response rate to subsequent therapy was only 26%, the complete response rate was 7%, and the median overall survival time was only 6.3 months. Hence effective therapies for primary refractory DLBCL, such as those described in the next paragraph, remain eagerly awaited.

Early studies of cellular therapy with genetically modified chimeric antigen receptor (CAR) T cells have shown some promise for patients with primary refractory DLBCL. In the ZUMA-1 trial, autologous anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) led to a complete response rate of 58% and an overall response rate of 83% among patients with relapsed/refractory DLBCL, with 39% of patients maintaining those responses at a median follow-up time of 27 months.45,46 Encouraging clinical responses in muticenter trials of the axi-cel preparation, and subsequent trials of the tisagenleclucel ciloleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) compounds, led to approval of the compounds by the US Food and Drug Administration for patients with relapsed/refractory aggressive large B-cell lymphomas.47,48 Although CAR T-cell therapy has revolutionized the treatment approach to relapsed/refractory DLBCL, opportunities still exist for improvement in treatment toxicity and response durability, and coupling RT with CAR T-cell therapy may offer additional opportunities to improve outcomes.

Several studies provide early evidence that RT can be a safe and effective bridging treatment for patients who require therapy to maintain disease control and minimize morbidity from disease progression during the CAR T-cell manufacturing process. Reported single-institution series of patients thus “bridged” with RT before CAR T-cell infusion include those from Moffitt Cancer Center,49 MD Anderson Cancer Center,50 and the University of Pennsylvania.51 The Moffitt study,49 in which 11 patients received axi-cel infusion after RT bridging, led to an overall response rate of 81.8% among evaluable patients and a complete response rate of 45% at a median follow-up time of 3.3 months. Severe (grade ≥3) cytokine release syndrome or immune effector-cell-associated neurotoxicity syndrome was experienced by 27% of patients, a rate no higher than that among patients in non-RT-bridged studies. In the MD Anderson study,50 11 patients bridged with RT alone had a progression-free survival rate of 44% at 1 year, which was comparable to that for 62 patients who did not receive bridging therapy (44%, p = 0.52). The overall response rate (100%) and complete response rate (82%) were higher for the 11 patients bridged with RT only than for the 45 patients bridged with systemic therapy only (67 and 38%, respectively, p = 0.01). Collectively, these published series suggest that single-modality RT can be an effective bridging option for patients awaiting CAR T-cell treatment. The optimal radiation dose and target to be used for this indication remain unknown and are under active investigation

In addition to RT as a bridging regimen to avoid symptomatic progression, RT may also be an attractive salvage therapy option for patients with disease progression after CAR T-cell therapy, as was described in an early retrospective series of 14 patients treated with salvage RT for whom the median overall survival time was 10 months, with 3 patients successfully bridged to allogeneic transplant.52

Perhaps one of the most appealing future applications of RT in the CAR-T setting is that of potential immunologic modulation and priming of CAR-T cell function. Early preclinical evidence shows that low-dose RT induces tumor cell susceptibility to CAR-T-cell-mediated TRAIL-apoptotic death.53 RT is also known to augment cytotoxic T-cell migration, to reverse T-cell exhaustion, and to diversify the T-cell receptor repertoire of tumor-infiltrating lymphocytes.54 Whether RT can effectively prime CAR-T-cell function either before infusion or in early salvage therapy is a pivotal question that merits clinical investigation.

Conclusions

Collectively, findings from recent and ongoing studies provide strong support for the idea that RT can be helpful for patients with resistant primary refractory or relapsed DLBCL. As future investigations continue, therapies for controlling disease, those for preventing relapse or resistance, and use of RT for augmenting immune and cellular therapies will continue to evolve to aid patients with relapsed disease.

Footnotes

Acknowledgment: The authors would like to thank Christine Wogan from the Department of Radiation Oncology for critical review and editing of the manuscript.

Disclaimers: The authors declare no conflicts of interest related to this work.

Funding: This study was supported in part by Cancer Center Core (Support) Grant CA016672 from the National Cancer Institute, National Institutes of Health, to The University of Texas MD Anderson Cancer Center.

Contributor Information

Eric D. Brooks, Email: eric.brooks@ufl.edu.

Penny Fang, Email: PFang@mdanderson.org.

Chelsea C. Pinnix, Email: ccpinnix@mdanderson.org.

REFERENCES

  • 1.Hunt KE, Reichard KK. Diffuse large B-cell lymphoma. Arch Pathol Lab Med 2008; 132: 118–24. doi: 10.5858/2008-132-118-DLBL [DOI] [PubMed] [Google Scholar]
  • 2.Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. Chop chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–42. doi: 10.1056/NEJMoa011795 [DOI] [PubMed] [Google Scholar]
  • 3.Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program 2012; 2012: 402–9. doi: 10.1182/asheducation.V2012.1.402.3798516 [DOI] [PubMed] [Google Scholar]
  • 4.Maurer MJ, Ghesquières H, Link BK, Jais J-P, Habermann TM, Thompson CA, et al. Diagnosis-to-Treatment interval is an important clinical factor in newly diagnosed diffuse large B-cell lymphoma and has implication for bias in clinical trials. J Clin Oncol 2018; 36: 1603–10. doi: 10.1200/JCO.2017.76.5198 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood 2015; 125: 22–32. doi: 10.1182/blood-2014-05-577189 [DOI] [PubMed] [Google Scholar]
  • 6.Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International prognostic index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109: 1857–61. doi: 10.1182/blood-2006-08-038257 [DOI] [PubMed] [Google Scholar]
  • 7.Pfreundschuh M, Ho AD, Cavallin-Stahl E, Wolf M, Pettengell R, Vasova I, et al. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera international trial Group (mint) study. Lancet Oncol 2008; 9: 435–44. doi: 10.1016/S1470-2045(08)70078-0 [DOI] [PubMed] [Google Scholar]
  • 8.Delaby G, Hubaut M-A, Morschhauser F, Besson A, Huglo D, Herbaux C, et al. Prognostic value of the metabolic bulk volume in patients with diffuse large B-cell lymphoma on baseline 18F-FDG PET-CT. Leuk Lymphoma 2020; 61: 1584–91. doi: 10.1080/10428194.2020.1728750 [DOI] [PubMed] [Google Scholar]
  • 9.Friedberg JW. Double-hit diffuse large B-cell lymphoma. J Clin Oncol 2012; 30: 3439–43. doi: 10.1200/JCO.2012.43.5800 [DOI] [PubMed] [Google Scholar]
  • 10.Rosenthal A, Younes A. High grade B-cell lymphoma with rearrangements of myc and Bcl2 and/or BCL6: double hit and triple hit lymphomas and double expressing lymphoma. Blood Rev 2017; 31: 37–42. doi: 10.1016/j.blre.2016.09.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Friedberg JW. Relapsed/Refractory diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program 2011; 2011: 498–505. doi: 10.1182/asheducation-2011.1.498 [DOI] [PubMed] [Google Scholar]
  • 12.National Comprehensive Cancer Network Diffuse large B cell lymphoma: NCCN guidelines. 2021;.
  • 13.Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, et al. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood 2018; 131: 174–81. doi: 10.1182/blood-2017-07-793984 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Grass GD, Mills MN, Ahmed KA, Liveringhouse CL, Montejo ME, Robinson TJ, et al. Radiotherapy for early stage diffuse large B-cell lymphoma with or without double or triple hit genetic alterations. Leuk Lymphoma 2019; 60: 886–93. doi: 10.1080/10428194.2018.1506586 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Stephens DM, Li H, LeBlanc ML, Puvvada SD, Persky D, Friedberg JW, et al. Continued risk of relapse independent of treatment modality in limited-stage diffuse large B-cell lymphoma: final and long-term analysis of Southwest Oncology Group study S8736. J Clin Oncol 2016; 34: 2997–3004. doi: 10.1200/JCO.2015.65.4582 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Held G, Murawski N, Ziepert M, Fleckenstein J, Pöschel V, Zwick C, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 2014; 32: 1112–8. doi: 10.1200/JCO.2013.51.4505 [DOI] [PubMed] [Google Scholar]
  • 17.Held G, Zeynalova S, Murawski N, Ziepert M, Kempf B, Viardot A, et al. Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement. J Clin Oncol 2013; 31: 4115–22. doi: 10.1200/JCO.2012.48.0467 [DOI] [PubMed] [Google Scholar]
  • 18.Imber BS, Yahalom J. Radiotherapy for non-Hodgkin lymphomas. Cancer J 2020; 26: 217–30. doi: 10.1097/PPO.0000000000000453 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Vargo JA, Gill BS, Balasubramani GK, Beriwal S. Treatment selection and survival outcomes in early-stage diffuse large B-cell lymphoma: do we still need consolidative radiotherapy? J Clin Oncol 2015; 33: 3710–7. doi: 10.1200/JCO.2015.61.7654 [DOI] [PubMed] [Google Scholar]
  • 20.Bonnet C, Fillet G, Mounier N, Ganem G, Molina TJ, Thiéblemont C, et al. Chop alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2007; 25: 787–92. doi: 10.1200/JCO.2006.07.0722 [DOI] [PubMed] [Google Scholar]
  • 21.Horning SJ, Weller E, Kim K, Earle JD, O'Connell MJ, Habermann TM, 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: 3032–8. doi: 10.1200/JCO.2004.06.088 [DOI] [PubMed] [Google Scholar]
  • 22.Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, 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: 21–6. doi: 10.1056/NEJM199807023390104 [DOI] [PubMed] [Google Scholar]
  • 23.Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005; 352: 1197–205. doi: 10.1056/NEJMoa042040 [DOI] [PubMed] [Google Scholar]
  • 24.Ferreri AJ, Dell'Oro S, Reni M, Ceresoli GL, Cozzarini C, Ponzoni M, et al. Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas. Oncology 2000; 58: 219–26. doi: 10.1159/000012104 [DOI] [PubMed] [Google Scholar]
  • 25.Kahn ST, Flowers C, Lechowicz MJ, Hollenbach K, Johnstone PAS. Value of PET restaging after chemotherapy for non-Hodgkin's lymphoma: implications for consolidation radiotherapy. Int J Radiat Oncol Biol Phys 2006; 66: 961–5. doi: 10.1016/j.ijrobp.2006.07.1365 [DOI] [PubMed] [Google Scholar]
  • 26.Schlembach PJ, Wilder RB, Tucker SL, Ha CS, Rodriguez MA, Hess MA, et al. Impact of involved field radiotherapy after CHOP-based chemotherapy on stage III-IV, intermediate grade and large-cell immunoblastic lymphomas. Int J Radiat Oncol Biol Phys 2000; 48: 1107–10. doi: 10.1016/S0360-3016(00)00760-4 [DOI] [PubMed] [Google Scholar]
  • 27.Dabaja BS, Vanderplas AM, Crosby-Thompson AL, Abel GA, Czuczman MS, Friedberg JW, et al. Radiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National comprehensive cancer network lymphoma outcomes project. Cancer 2015; 121: 1032–9. doi: 10.1002/cncr.29113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Hu C, Deng C, Zou W, Zhang G, Wang J. The role of consolidative radiotherapy after a complete response to chemotherapy in the treatment of diffuse large B-cell lymphoma in the rituximab era: results from a systematic review with a meta-analysis. Acta Haematol 2015; 134: 111–8. doi: 10.1159/000370096 [DOI] [PubMed] [Google Scholar]
  • 29.Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI sponsored international Working group. J Clin Oncol 1999; 17: 1244. doi: 10.1200/JCO.1999.17.4.1244 [DOI] [PubMed] [Google Scholar]
  • 30.Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, et al. 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: 2271–81. doi: 10.1016/S0140-6736(19)33008-9 [DOI] [PubMed] [Google Scholar]
  • 31.Pinnix CC, Gunther JR, Fang P, Bankston ME, Milgrom SA, Boyce D, et al. Assessment of radiation doses delivered to organs at risk among patients with early-stage favorable Hodgkin lymphoma treated with contemporary radiation therapy. JAMA Netw Open 2020; 3: e2013935: e2013935. doi: 10.1001/jamanetworkopen.2020.13935 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Illidge T, Specht L, Yahalom J, Aleman B, Berthelsen AK, Constine L, et al. Modern radiation therapy for nodal non-Hodgkin lymphoma-target definition and dose guidelines from the International lymphoma radiation Oncology Group. Int J Radiat Oncol Biol Phys 2014; 89: 49–58. doi: 10.1016/j.ijrobp.2014.01.006 [DOI] [PubMed] [Google Scholar]
  • 33.Bartlett NL, Wilson WH, Jung S-H, Hsi ED, Maurer MJ, Pederson LD, et al. Dose-Adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III intergroup trial Alliance/CALGB 50303. J Clin Oncol 2019; 37: 1790–9. doi: 10.1200/JCO.18.01994 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Dunleavy K, Fanale MA, Abramson JS, Noy A, Caimi PF, Pittaluga S, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with Myc rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet Haematol 2018; 5: e609–17. doi: 10.1016/S2352-3026(18)30177-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995; 333: 1540–5. doi: 10.1056/NEJM199512073332305 [DOI] [PubMed] [Google Scholar]
  • 36.Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–90. doi: 10.1200/JCO.2010.28.1618 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Hoppe BS, Moskowitz CH, Zhang Z, Maragulia JC, Rice RD, Reiner AS, et al. The role of FDG-PET imaging and involved field radiotherapy in relapsed or refractory diffuse large B-cell lymphoma. Bone Marrow Transplant 2009; 43: 941–8. doi: 10.1038/bmt.2008.408 [DOI] [PubMed] [Google Scholar]
  • 38.Dhakal S, Bates JE, Casulo C, Friedberg JW, Becker MW, Liesveld JL, et al. Patterns and timing of failure for diffuse large B-cell lymphoma after initial therapy in a cohort who underwent autologous bone marrow transplantation for relapse. Int J Radiat Oncol Biol Phys 2016; 96: 372–8. doi: 10.1016/j.ijrobp.2016.05.021 [DOI] [PubMed] [Google Scholar]
  • 39.Persky DO, Li H, Stephens DM, Park SI, Bartlett NL, Swinnen LJ, 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: 3003–11. doi: 10.1200/JCO.20.00999 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Freeman CL, Savage KJ, Villa DR, Scott DW, Srour L, Gerrie AS, et al. Long-Term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP. Blood 2021; 137: 929–38. doi: 10.1182/blood.2020005846 [DOI] [PubMed] [Google Scholar]
  • 41.Ng AK, Yahalom J, Goda JS, Constine LS, Pinnix CC, Kelsey CR, et al. Role of radiation therapy in patients with relapsed/refractory diffuse large B-cell lymphoma: guidelines from the International lymphoma radiation Oncology Group. Int J Radiat Oncol Biol Phys 2018; 100: 652–69. doi: 10.1016/j.ijrobp.2017.12.005 [DOI] [PubMed] [Google Scholar]
  • 42.Kelsey CR, Broadwater G, James O, Chino J, Diehl L, Beaven AW, et al. Phase 2 study of Dose-Reduced consolidation radiation therapy in diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys 2019; 105: 96–101. doi: 10.1016/j.ijrobp.2019.02.055 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Tseng YD, Chen Y-H, Catalano PJ, Ng A. Rates and durability of response to salvage radiation therapy among patients with refractory or relapsed aggressive non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2015; 91: 223–31. doi: 10.1016/j.ijrobp.2014.09.041 [DOI] [PubMed] [Google Scholar]
  • 44.Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the International SCHOLAR-1 study. Blood 2017; 130: 1800–8. doi: 10.1182/blood-2017-03-769620 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017; 377: 2531–44. doi: 10.1056/NEJMoa1707447 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-Term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 2019; 20: 31–42. doi: 10.1016/S1470-2045(18)30864-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019; 380: 45–56. doi: 10.1056/NEJMoa1804980 [DOI] [PubMed] [Google Scholar]
  • 48.Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, 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: 839–52. doi: 10.1016/S0140-6736(20)31366-0 [DOI] [PubMed] [Google Scholar]
  • 49.Sim AJ, Jain MD, Figura NB, Chavez JC, Shah BD, Khimani F, et al. Radiation therapy as a bridging strategy for CAR T cell therapy with Axicabtagene Ciloleucel in diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys 2019; 105: 1012–21. doi: 10.1016/j.ijrobp.2019.05.065 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Pinnix CC, Gunther JR, Dabaja BS, Strati P, Fang P, Hawkins MC, et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. Blood Adv 2020; 4: 2871–83. doi: 10.1182/bloodadvances.2020001837 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Wright CM, LaRiviere MJ, Baron JA, Uche C, Xiao Y, Arscott WT, et al. Bridging radiation therapy before commercial chimeric antigen receptor T-cell therapy for relapsed or refractory aggressive B-cell lymphoma. Int J Radiat Oncol Biol Phys 2020; 108: 178–88. doi: 10.1016/j.ijrobp.2020.05.014 [DOI] [PubMed] [Google Scholar]
  • 52.Imber BS, Sadelain M, DeSelm C, Batlevi C, Brentjens RJ, Dahi PB, et al. Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy. Br J Haematol 2020; 190: 45–51. doi: 10.1111/bjh.16541 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.DeSelm C, Palomba ML, Yahalom J, Hamieh M, Eyquem J, Rajasekhar VK, et al. Low-Dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther 2018; 26: 2542–52. doi: 10.1016/j.ymthe.2018.09.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373–7. doi: 10.1038/nature14292 [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The British Journal of Radiology are provided here courtesy of Oxford University Press

RESOURCES