Involved Site Radiation Therapy Research Articles

Effective bridging strategies prior to infusion with tisagenlecleucel results in high response rates and long-term remission in relapsed/refractory large B-cell lymphoma: findings from a German monocentric study

BackgroundIncorporating chimeric antigen receptor (CAR)-T cell therapy into relapsed or refractory large B-cell lymphoma (rr LBCL) treatment algorithms has yielded remarkable response rates and durable remissions, yet a substantial portion of patients experience progression or relapse. Variations in outcomes across treatment centers may be attributed to different bridging strategies and remission statuses preceding CAR-T cell therapy.PatientsTwenty-nine consecutive adult patients receiving tisagenlecleucel (tisa-cel) for rr LBCL from December 2019 to February 2023 at Jena University Hospital were analyzed.ResultsThe median age was 63, with a median of 3 prior treatments. Twenty patients (69%) were refractory to any systemic therapy before CAR-T cell treatment. Following leukapheresis, 25 patients (86%) received bridging therapy with the majority undergoing chemotherapy (52%) or combined modality therapy (32%). Radiotherapy (RT) was part of the bridging strategy in 44%, with moderately hypofractionated involved site RT (30.0 Gy/2.5 Gy) being applied most frequently (64%). Post-CAR-T infusion, the objective response rate at 30 days was 83%, with 55% achieving complete response. Twelve-month progression-free (PFS) and overall survival (OS) were 60% and 74%, respectively, with a median follow up of 11.1 months for PFS and 17.9 months for OS. Factors significantly associated with PFS were chemotherapy sensitivity pre-leukapheresis and response to bridging.ConclusionThe study underscores the importance of minimal tumor burden at CAR-T initiation, emphasizing the need for suitable bridging regimens. The findings advocate for clinical trials and further real-world analyses to optimize CAR-T cell therapy outcomes by identifying the most effective bridging strategies.

Knowledge and competences in hematological malignancies amongst radiation oncology residents in Germany-results from anational survey.

Radiation oncology is apivotal modality in the treatment of hematologic malignancies. To enable state-of-the-art patient care, structured education during residency is essential. However, given the lack of detailed data, the scope of educational opportunities available to trainees remains elusive. This prompted our group to perform anational survey amongst radiation oncology residents in Germany assessing the status quo of competences in the treatment of lymphoma and leukemia patients. Furthermore, areas of potential improvement were identified to further the goal of competence-based education for residents. Asurvey-based analysis was conducted to assess the knowledge and competence of radiation oncology residents in Germany regarding hematological malignancies. Adecisive questionnaire covering demographics, self-assessment of competences, and areas for improvement was developed in adaption of asurvey by the Association of Residents in Radiation Oncology and distributed amongst 1439 members of the German Society of Radiation Oncology. Responses were collected anonymously via an online survey tool and analyzed using descriptive statistics and chi-square tests. Atotal of 59complete and 22partial responses were collected, yielding a5.6% response rate. Participants' competence varied, with notable experience gaps in pediatric cases, proton therapy, and large-field techniques like total-skin irradiation or pediatric total body irradiation. While participants felt confident in treatment planning and patient counseling, they showed deficiencies in the definition of the planning target volume for modern involved site radiotherapy. Resources for education included national and international guidelines, scientific reviews, and textbooks. Board-certified radiation oncologists and physicians from specialized lymphoma centers demonstrated higher overall competence levels. This survey highlights the diversity of resident education regarding hematological malignancies in German radiation oncology programs. Knowledge gaps exist in key areas, including pediatric cases and specialized techniques. Competence-based education, interactive teaching formats, and rotations to specialized centers are potential strategies to address these gaps. The study contributes to the understanding of the federal educational landscape, underscoring the need for standardized and comprehensive training to ensure optimal patient care in hematological malignancies within the context of radiation oncology. Further research and collaborations are warranted to enhance training and expertise in this critical domain.

Involved-site Radiation Therapy is Equally Effective and Less Toxic Than Involved-field Radiation Therapy in Patients Receiving Combined Modality Treatment for Early-stage Unfavorable Hodgkin Lymphoma—An Analysis of the Randomized Phase 3 HD17 Trial of the German Hodgkin Study Group

PurposeCombined modality treatment (CMT) with chemotherapy followed by consolidation radiotherapy (RT), provides excellent outcomes for patients with early-stage Hodgkin lymphoma (HL). The international standard of care for consolidation RT, involved-site/involved-node radiotherapy (ISRT/INRT), has never been evaluated in a randomized phase III trial against the former standard involved-field radiotherapy (IFRT). Methods and materialsIn the multicenter phase III AnonymizedStudyGroupXXX AnonymizedStudyYYY trial, patients with early stage unfavorable HL were randomized between the standard CMT group and a positron-emission tomography (PET) -guided group. In the standard group, patients received two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gray (Gy) IFRT. In the experimental group patients received no further therapy if post-chemotherapy PET was negative, and 30 Gy AnonymizedStudyGroupXXX -INRT, comparable and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT. Results1,100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival (PFS) were 96.8 % (95% CI: 91.6% – 98.8%) in the IFRT group and 95.4% (95% CI: 89.9% – 97.9%; HR: 1.40, 95% CI: 0.44 – 4.42) in the ISRT group. Pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade III/IV toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (p=0.03). ConclusionsFor the first time, consolidation INRT/ISRT was randomly compared to IFRT in a phase III trial. Regarding PFS, no advantage for IFRT could be demonstrated. In summary, our data confirm the place of INRT/ISRT as the current standard of care.

Long-Term Results of IFRT vs. ISRT in Infradiaphragmal Fields in Aggressive Non-Hodgkins’s Lymphoma Patients—A Single Centre Experience

(1) Background: This study aimed to examine the difference in efficacy and toxicity of involved-field (IFRT) and involved-site radiotherapy (ISRT) fields in infradiaphragmal aggressive non-Hodgkin lymphoma patients. (2) Methods: In total, 140 patients with infradiaphragmal lymphoma treated between 2003 and 2020 were retrospectively evaluated. There were 69 patients (49%) treated with IFRT, and 71 (51%) patients treated with ISRT. The median dose in the IFRT group was 36 Gy, (range 4–50.4 Gy), and in the ISRT group, it was 30 Gy (range 4–48 Gy). (3) Results: The median follow-up in the IFRT group was 133 months (95% CI 109–158), and in the ISRT group, it was 48 months (95% CI 39–57). In the IFRT group, locoregional control was 67%, and in the ISRT group, 73%. The 2- and 5-year overall survival (OS) in the IFRT and ISRT groups were 79% and 69% vs. 80% and 70%, respectively (p = 0.711). The 2- and 5-year event-free survival (EFS) in the IFRT and ISRT groups were 73% and 68% vs. 77% and 70%, respectively (p = 0.575). Acute side effects occurred in 43 (31%) patients, which is more frequent in the IFRT group, 34 (39%) patients, than in the ISRT group, 9 (13%) patients, p > 0.01. Late toxicities occurred more often in the IFRT group of patients, (10/53) 19%, than in the ISRT group of patients, (2/37) 5%, (p = 0.026). (4) Conclusions: By reducing the radiotherapy volume and the doses in the treatment of infradiaphragmatic fields, treatment with significantly fewer acute and long-term side effects is possible. At the same time, efficiency and local disease control are not compromised.

Predicting long‑term survival following involved site radiotherapy for oligometastases.

The majority of cancer-associated mortalities are due to distant metastases, and systemic therapy alone is generally not curative. Patients with oligometastases are amenable to involved site radiotherapy with the possibility of long-term disease-free survival; however, prognostic factors remain poorly defined. The present retrospective, single institution study consisted of consecutive adult patients with oligometastases from solid tumor malignancy referred to a single high volume radiation oncologist between January 2014 and December 2021. Oligometastases were defined as ≤5 extracranial or intracranial metastatic lesions where all sites of active disease are treatable, including patients requiring treatment of the primary tumor and/or regional lymph nodes. The study population consisted of 130 patients with 207 treated distant metastases. Radical radiotherapy was administered to all areas of known residual disease and included stereotactic radiotherapy (median dose, 27 Gy in 3 fractions) or intensity modulated radiotherapy (median dose, 50 Gy in 15 fractions). At a median follow-up of 28.8 months, the median overall survival was 37.9 months with a 4-year overall survival of 41.1%. The median progression-free survival was 12.3 months and the 4-year progression-free survival was 22.6%. On multivariate an1alysis, the strongest predictors of overall survival were age, ECOG performance status, primary prostate, breast or kidney tumor and pre-radiation serum albumin (P≤0.01 for all). Overall, the present study demonstrated that long-term overall survival was possible after radical treatment for oligometastases and identified potential prognostic factors.

Motion Management: The Road Map to Accurate Radiation Treatment Delivery

Radiation therapy is a key contributor to positive outcomes in hematological malignancies. However, this is contingent on minimizing the exposure of critical normal organs. The introduction of computed tomography (CT) for radiation treatment planning and the development of sophisticated dose calculation algorithms has transformed the radiation therapy field and made it possible to transition from conventional involved-field radiation to modern involved-site radiation therapy. Thanks to rapid advances in drug discovery, treatment strategies for many hematological malignancies have evolved to incorporate targeted and cellular therapies, in some cases even allowing the replacement of chemotherapy. As a result, new opportunities have been created for radiation to address relapses after more lines of therapy, identify disease-involving sanctuary sites, and bridge to the subsequent therapy. When considering radiation in patients receiving novel therapies, who may also be more heavily pretreated, respecting the critical and normal structures at all costs is imperative. In this document, we will describe modern techniques used to deliver state-of-the-art radiation therapy and practical considerations to ensure the accurate treatment of the target while avoiding normal organs at risk.

Impact of Modern Low Dose Involved Site Radiation Therapy on Normal Tissue Toxicity in Cervicothoracic Non-Hodgkin Lymphomas: A Biophysical Study.

This biophysical study aimed to determine fitting parameters for the Lyman-Kutcher-Burman (LKB) dose-response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24-54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5-45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose-response models properly predicted the patient's probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today's reduced radiation doses in the treatment of NHL.

Long-term disease-free survival following comprehensive involved site radiotherapy for oligometastases.

Despite recent advances in drug development, durable complete remissions with systemic therapy alone for metastatic cancers remain infrequent. With the development of advanced radiation technologies capable of selectively sparing normal tissues, patients with oligometastases are often amenable to comprehensive involved site radiotherapy with curative intent. This study reports the long-term outcomes and patterns of failure for patients treated with total metastatic ablation often in combination with systemic therapy. Consecutive adult patients with oligometastases from solid tumor malignancy treated by a single high volume radiation oncologist between 2014 and 2021 were retrospectively analyzed. Oligometastases were defined as 5 or fewer metastatic lesions where all sites of active disease are amenable to local treatment. Comprehensive involved site radiotherapy consisted of stereotactic radiotherapy to a median dose of 27 Gy in 3 fractions and intensity modulated radiation therapy to a median dose of 50 Gy in 15 fractions. This study analyzed overall survival, progression-free survival, patterns of failure and toxicity. A total of 130 patients with 209 treated distant metastases were treated with a median follow-up of 36 months. The 4-year overall survival, progression-free survival, local control and distant control was 41%, 23%, 86% and 29%. Patterns of failure include 23% alive and free of disease (NED), 52% distant failure only, 9% NED but death from comorbid illness, 7% both local and distant failure, 4% NED but lost to follow-up, 4% referred to hospice before restaging, 1% local only failure, 1% alive with second primary cancer. Late grade 3+ toxicities occurred in 4% of patients, most commonly radionecrosis. Involved site radiotherapy to all areas of known disease can safely achieve durable complete remissions in patients with oligometastases treated in the real world setting. Distant failures account for the majority of treatment failures and isolated local failures are exceedingly uncommon. Oligometastases represents a promising setting to investigate novel therapeutics targeting minimal residual disease.

Ultra-Hypofractionated Involved Site Radiation Therapy (ISRT) As Salvage or Bridging Therapy in Aggressive Non-Hodgkin Lymphomas

Introduction: Conventional fractionated radiation treatment (RT) to a total dose of 40-50 Gy in 20-25 fractions is typically recommended in the ‘definitive’ intent treatment of aggressive chemorefractory non-Hodgkin lymphoma. However, during the time of COVID-19, recommendations for hypofractionated courses (5-13 fractions) arose (Yahalom et al Blood 2020) as modern radiation techniques should allow similar total doses to be delivered safely in far fewer fractions. Our aim is to evaluate the outcomes and toxicities of ultra-hypofractionated (</=5 fractions) ‘definitive’ ISRT in aggressive non-Hodgkin lymphomas to see if this may be an acceptable alternate recommendation beyond COVID-19. Methods: We conducted an IRB-approved, retrospective review of all aggressive non-Hodgkin lymphoma patients treated at our institution with ‘definitive’ intent (40-50 Gy EQD2 with an α/β of 10) ultra-hypofractionated ISRT between April 2020 and July 2023. Demographic, disease-specific, and treatment-related variables were collected. Primary outcomes include objective response rate (ORR), defined as complete (CR) or partial response (PR) on post-RT positron emission tomography (PET) scans using the Lugano classification, local failure (LF), and radiation-related toxicity per CTCAE v5. Secondary outcomes include overall disease control and survival. Results: 26 ultra-hypofractionated radiation treatments were identified from 23 unique patients who were treated with ‘definitive’ intent ISRT (39.1% salvage, 30.4% early-salvage post CAR-T, and 30.4% bridging to SCT or CAR-T). The most common dose was 30 Gy in 5 fractions (96%); all patients were treated with IMRT with SBRT-type immobilization and image guidance as clinically indicated. The most common diagnosis was DLBCL (91%). 10/23 (43%) patients were female, the majority (82%) were ECOG 0-1 performance status, and the average age at time of RT was 68.9 years. 39% had all FDG-avid sites at the time of radiation treated. The median follow-up was 8.3 months (range 0.3-27.9 months). 26% of patients had acute radiation related toxicities, which were all grade 1-2 with the most common being fatigue (30%). There were no grade 3-4 toxicities, and no subacute or long-term toxicities. Initial local ORR was 20/21, or 95% (86% CR and 10% PR), while initial overall ORR was 12/21, or 57% (52% CR and 5% PR). At time of last follow up, only 1/24 (4%) of irradiated sites had local failure (2 data points N/A), with a TTLF of 1.5 months. 62% of patients had disease progression, with median time to disease progression of 1.5 months. At time of last follow up, 48% were dead, with a median time to death of 6.6 months. Conclusions: Ultra-hypofractionated ISRT in the ‘definitive’ intent treatment of aggressive non-Hodgkin lymphomas has excellent local tumor control and appears to be safe with minimal acute and subacute toxicities. In addition to patient convenience and cost effectiveness, short-course ISRT allows patients to quickly move on to next-line therapy when indicated. Prospective studies and long-term follow up are needed to further validate this as an alternative radiation treatment option.

Radiation Therapy in the Management of Primary Gastric Diffuse Large B-Cell Lymphomas: Long-Term Outcomes of 82 Patients

Background/Objectives: Our group has recently published its long-term experience treating gastric MALT lymphomas with involved site radiation therapy (ISRT) and supported the use of RT alone as standard of care for H pylori independent MALT. For primary gastric (PG) diffuse large B-cell lymphomas (DLBCL), R-CHOP is the mainstay of therapy, but RT to the stomach primarily as consolidation has rarely been analyzed. In this study, we focus on pts with PG DLBCL who received combined modality therapy. Materials/Methods: 285 consecutive pts with PG lymphomas treated with RT between 1/2000-1/2021 at our institution were retrospectively identified. Baseline characteristics and follow-up data were abstracted. Overall response rate (ORR) was assessed with Lugano PET criteria and endoscopy. Overall survival (OS) was calculated using Kaplan-Meier. Toxicity was assessed with CTCAE v4.0. Results: Of 285 pts, 203 (71%) had PG MALT and 82 (29%) PG DLBCL. Baseline characteristics are summarized in Table 1. In the DLBCL pts, 74 (90%) received consolidation RT after limited (3-4 cycles) or full (6 cycles) chemoimmunotherapy (CT), 4 (5%) received RT after 2 lines of CT, 2 (3%) received first line RT followed by CT, 1 (1%) had 3 lines of CT and RT, and 1 (1%) was treated with surgery, 2 lines of CT, and RT. In the 74 pts who received CT+RT as first line treatment, the median RT dose was 3060 cGy (range 1620-3600). Based on post-chemo pre-RT EGD and PET, 61 (82%) pts were in CR, 7 (10%) had PR, 3 (4%) had SD and 3 (4%) pts were not assessed. Overall, 66 (89%) pts who received RT after CT achieved a CR. Of the remaining 8 (11%) pts who did not achieve a CR after RT, 4 had PR, 1 had SD, 1 was lost to FU, 1 started additional CT before response assessment and 1 pt died. The 2 pts in the DLBCL group who received first line RT achieved CR after RT. Side effects after RT were mild and limited to nausea and fatigue. The median follow-up time was 5.4 years (95% CI 0.4, 20.4) in DLBCL pts and 6.3 yrs (95% CI 0.3, 22.1) in MALT pts. The 5-year OS was 80% (95% CI 71-90%) for DLBCL and 96% (95% CI 93-99%) for MALT. Conclusion: Adding stomach RT following chemoimmunotherapy is feasible, well-tolerated and safe. More in depth analysis PG DLBCL is underway, with a plan to compare outcomes of patients treated with CT alone versus CT followed by RT, and further analyze treatment-related toxicities, progression-free survival, and patterns of recurrence.

Activity and Event-Free Survival in Intermediate Grade Non-Hodgkin's Lymphoma Treated with Chemoimmunotherapy Utilizing Single Dose Intravenous Methylprednisolone in Lieu of Oral Prednisone

Schein et al first noted that patients with intermediate grade lymphoma treated with combination chemotherapy leading to complete response lasting 24 months were likely to remain relapse-free (Schein, Chabner, Canellos, Young, Berard, DeVita,1975). Subsequent changes in that original C-MOPP regimen have included the use of anthracyclines and rituximab. The University of Iowa/Mayo Clinic Molecular Epidemiology Resource and the Groupe d'Etude des Lymphomes de l'Adulte (GELA) program found that patients with diffuse large B-cell lymphoma achieving event-free status at 24 months with chemoimmunotherapy have subsequent overall survival equivalent to that of the general population (Maurer, 2014). While Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Prednisone (RCHOP) has served as the reference therapy for intermediate grade non-Hodgkin's lymphoma for two decades (Coiffier, 2002; Pfreundschuh, 2006), oral prednisone given daily for 5 days is problematic for individuals with underlying medical conditions such as diabetes, sleep or psychiatric disorders, or gastrointestinal symptoms. In this retrospective study between January, 2007 and March, 2023, 33 patients with intermediate grade Non-Hodgkin's Lymphoma, (26 with Diffuse Large B-cell subtype, 6 with follicular grade III, 1 with T-cell Immunoblastic) received Methylprednisolone 125 mg intravenously on day 1 instead of oral prednisone for 5 days as part of anthracycline-based treatment that consisted of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Three patients received mitoxantrone 12 mg/m2 intravenously on day 1 instead of doxorubicin. Patient characteristics: 23 males/10 females, median age-55 (range: 24-85), stages: IV (17 patients), III (4 patients), II (12 patients), B symptoms (16), subtypes: non-germinal center (13), germinal center (12), diffuse B-cell NOS (1), follicular grade III (6), T-cell Immunoblastic (1). Median cycles received (range): 6 (5-8). No patients required dose reduction or omission of methylprednisolone. Complete responses (determined by PET/CT) occurred in 26 (81%). 1 additional patient was PET negative but was lost to follow-up and is not counted as CR here. Three patients having PR after chemoimmunotherapy were converted to CR after involved site radiation. Two other patients achieved only short-lived PR. One patient is too early to evaluate. The median event-free survival has not been reached at 24.8+ months. Median overall survival exceeds 32.6+ months. Chemoimmunotherapy with the substitution of intravenous methylprednisolone on day 1 in place of 5 days of oral prednisone displays activity in intermediate-grade non-Hodgkin lymphoma and event-free survival beyond 24 months.

AHOD2131: A Randomized Phase 3 Response-Adapted Trial Comparing Standard Therapy with Immuno-Oncology Therapy for Children and Adults with Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) >93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

Pembrolizumab (pembro) in Children and Young Adults with Low-Risk Classical Hodgkin Lymphoma (cHL) with Slow Early Response (SER) to Front-Line Chemotherapy (chemo): Early Results from the Phase 2 Keynote-667 Study

Background: Pediatric patients (pts) with low-risk cHL achieve high cure rates with standard chemo. However, those with a SER to front-line chemo are at higher risk of relapse than pts with a rapid early response (RER). Current treatment options are also associated with long-term toxicities such as secondary malignancies, cardiovascular disease, and pulmonary and gonadal toxicity. Novel treatment approaches are needed to optimize outcomes while minimizing long-term toxicity. KEYNOTE-667 (NCT03407144) is an open-label, phase 2 study that included an analysis of safety and efficacy of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) induction in pediatric pts with low-risk cHL followed by consolidation with pembro plus AVD and involved-site radiotherapy (ISRT) and pembro maintenance in those with SER to front-line ABVD. We present an interim analysis of pts with low-risk cHL enrolled in this trial. Methods: Eligible pts were 3-25 y old and had newly diagnosed stage IA, IB, or IIA cHL without bulky disease, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (aged <16 y) or a Karnofsky score of ≥50 (aged ≥16 y). Pts initially received 2 cycles of induction with ABVD. Response was then assessed by PET/MRI/CT (early response assessment). Pts with RER received nonstudy therapy per treating physician. Pts with SER (Deauville score [DS], 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) in combination with 2 cycles of AVD followed by a late response assessment (LRA) with PET/MRI/CT. All pts with a SER then received ISRT (21.6 Gy for pts with a complete PET response [DS, 1-3]; 30.6-36 Gy for pts with a partial PET response [DS, 4 or 5]) plus maintenance pembro Q3W for up to 17 cycles. Primary end point was ORR by blinded independent central review (BICR) per Cheson 2007 IWG criteria in pts with SER determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included rate of PET negativity after consolidation, EFS, OS, and safety. Results: 73 pts with low-risk cHL were enrolled, 9 of whom had SER to ABVD induction. 64 pts had a RER and received nonstudy treatment. At data cutoff (March 1, 2023), 2 of 9 pts (22%) with SER had completed consolidation and maintenance therapy, 5 (56%) were ongoing, and 2 (22%) had discontinued, both because of complete response. Median time from enrollment to data cutoff was 8.7 mo (range, 2.2-32.9). Median age was 16 y (range, 7-20), 5 pts (56%) were male, 2 (22%) had Ann Arbor stage I disease, and 7 (78%) had Ann Arbor stage II disease. Pts with SER had received a median of 8 doses of pembro (range, 1-17); median time on pembro was 4.8 mo (range, <0.1-11.3). Of 9 pts who received consolidation therapy with pembro plus AVD, 6 (67%) had a LRA (3 are still in consolidation and have not reached the LRA timepoint), of whom 3 (50%) were PET negative by BICR (2 [33%] were PET negative by investigator review). Of 73 pts who received ABVD induction, 66 (90%) had an AE regardless of causality. 33 pts (45%) experienced grade 3/4 AEs, most commonly (≥10%) neutrophil count decreased (n = 19; 26%) and neutropenia (n = 9; 12.3%). One pt experienced grade 4 febrile neutropenia. Twelve pts (16%) had serious AEs. No pts discontinued treatment or died because of AEs. Treatment-related AEs due to ABVD induction occurred in 59 pts (81%), with grade 3/4 events in 31 (42%). Of the 9 pts with SER to ABVD induction who received consolidation and maintenance therapy, 7 (78%) experienced an AE regardless of causality. Two pts (22%) had grade 3/4 AEs. No serious AEs were reported during consolidation and maintenance therapy, and no pts discontinued treatment or died because of AEs. Treatment-related AEs occurred in 6 pts (67%) who received consolidation and maintenance therapy; with grade 3/4 events in 2 pts (22%). Six pts (67%) experienced AEs related to pembro; most commonly (≥3 pts) anemia, nausea, vomiting (n = 3 each [33%]). Two pts experienced grade 3/4 AEs related to pembro (vomiting, white blood cell count decreased). One pt (11%) experienced an immune-mediated AE (grade 2 hyperthyroidism). Conclusion: Early results from the low-risk cHL cohort of KEYNOTE-667 suggest that induction therapy with ABVD and consolidation with pembro plus AVD had a manageable safety profile. Among the relatively small number of pts with a SER to ABVD, 50% with a LRA had a PET-negative response by BICR and received a reduced dose of RT.

Involved-site Radiotherapy Delineation Dilemmas in the Treatment of Adult Hodgkin Lymphoma: Turkish Society for Radiation Oncology Hematological Oncology, Pediatric Oncology and TBI Study Group Case-based Questionnaire Review (TROD 03-005)

AimsThe International Lymphoma Radiation Oncology Group (ILROG) defined involved-site radiotherapy (ISRT) guidelines. These rules offer a certain variability that allows for autonomous decision-making in diverse clinical settings. However, this flexibility also gives rise to conflicts about the selection of treatment fields in the daily decision-making process. The aim of this study was to show the extent of interobserver variability when ILROG-ISRT recommendations were used in different clinical scenarios. Materials and methodsThe 10-question survey used in our study consisted of two parts (part A and part B) and was prepared by four senior radiation oncologists experienced in the haemato-oncology field. The results were presented by stratifying according to clinical experience (<10 years, ≥10 years). Binomial tests (one-sided) were conducted to assess whether answers for each group and the whole group reached a consensus. ResultsTwenty-six radiation oncologists, 13 of whom had less than 10 years of experience and 13 seniors, participated in the survey. Eighty per cent of respondents thought ILROG did not bring sufficient solutions for all clinical scenarios but offered solutions in some cases. In different case-based scenarios, the consensus among the respondents decreased down to 38%. Senior radiation oncologists were found to have more doubts about the adequacy of current guidelines. ConclusionsILROG guidelines allow for a high degree of variability in real-life clinical scenarios and different interpretation of the recommendations may lead to increased toxicity and recurrences. Therefore, there is a need for refinement in ISRT delineation strategies. On behalf of the Turkish Society for Radiation Oncology Hematological Oncology, Pediatric Oncology and TBI Study Group, we are planning to carry out further educational contouring sessions to detect the interobserver variability in real-life contouring cases.

Fertility and Gonadal Function after First-Line Treatment with Nivolumab-AVD in Hodgkin Lymphoma Patients: An Analysis from the Phase II GHSG Nivahl Trial

Background: First-line treatment of patients with classical Hodgkin lymphoma (HL) with anti-PD1 antibodies in combination with AVD chemotherapy is highly effective across risk-groups. Based on encouraging phase II and ongoing phase III trials, anti-PD1 based first-line treatment may hence soon become a first-line treatment option. To date, no data on fertility and gonadal function after anti-PD1 based first-line HL treatment is available. Herein, we present data on pregnancies and gonadal function in patients treated within the randomized GHSG phase II NIVAHL trial. Methods: NIVAHL enrolled 109 patients aged 18-60 years with first diagnosis of early-stage unfavorable HL to receive either fully concomitant (4xN-AVD; group A) or sequential (4xN, 2xN-AVD, 2xAVD; group B) nivolumab-based 1st-line treatment, each followed by 30Gy involved-site radiotherapy (IS-RT). The primary and final analyses showed excellent efficacy and an acceptable safety profile after 1- and 3-years of follow up; details were previously published (Bröckelmann et al. JAMA Oncol 2020 &amp; JCO 2023). Data on pregnancies and births as well as sexual hormones prior, during and after treatment were collected via standardized case report forms. The cohort for this descriptive analysis included women &amp;lt;40 and men &amp;lt;50 years of age. Results: A total of 87 patients (55% female, 51% treatment group A) with a median age of 25 (range 18-49) were eligible for this analysis. Patient characteristics were well balanced between treatment groups and patients presented predominantly with stage IIA disease (75.3%) and presence of the risk factors ≥3 nodal areas (75%), elevated ESR (44%) and bulky mediastinal disease (20.2%). Cryopreservation prior start of treatment was performed in 39.6% of female and 74.4% of male patients. With a median follow-up (FU) of 41 months, a total of 11 pregnancies were documented (12.6%; 9 in female patients, 2 in partners of male patients). These resulted in 8 documented live births (2 abortions, 1 missing info), with none using assisted reproductive techniques. In female patients, median hormone levels remained relatively stable from baseline to 12-24 months of FU for FSH (4.7 -&amp;gt; 4.3 U/l), LH (6 -&amp;gt; 7.2 U/l) and AMH (2.3 -&amp;gt; 2.8 ug/l) while an increase of estradiol was observed (53.6 -&amp;gt; 102 ng/l). Similar trajectories of largely stable hormone levels were observed when stratifying female patients by age groups (i.e. 18-29 and 30-39 years). Women ≥30 years presented higher median FSH (6.1 vs 4.7 U/l) and lower estradiol values (48.8 vs 53.6 ng/l) compared to younger women at baseline, however, presented with similar median FSH levels at 12-24 months of FU (4.2 and 4.4 U/l, respectively). In male patients, hormone levels also remained stable from baseline to 12-24 months of FU for FSH (4.2 -&amp;gt; 4.2 U/l), LH (4.1 -&amp;gt; 3.9 U/l), testosterone (4 -&amp;gt; 5.6 ug/l) and inhibin B (159.4 -&amp;gt; 180 ng/l). More detailed analyses regarding hormonal trajectories of individual patients and stratifications by treatment group are ongoing and will be presented at the meeting. Conclusion: This analysis of pregnancies, births and sex hormones after first-line HL treatment with N-AVD indicates preserved gonadal function in the majority of both female and male patients.

Quality of Life with Nivolumab and AVD First-Line Treatment in Hodgkin Lymphoma: Patient-Reported Outcomes from the Phase II GHSG Nivahl Trial

Background: First-line treatment of patients with classical Hodgkin lymphoma (HL) with anti-PD1 antibodies in combination with AVD chemotherapy is highly effective across risk-groups. Based on encouraging phase II and ongoing phase III trials, anti-PD1 based first-line treatment may hence soon become a first-line treatment option. To date, no patient-reported outcome (PRO) data is available in this setting, which is crucial to comprehensively evaluate relative benefits of these novel treatment approaches. Herein, we present the preplanned PRO analysis of quality of life (QoL), fatigue and life situation of HL patients treated within the randomized GHSG phase II NIVAHL trial. Methods: NIVAHL enrolled 109 patients aged 18-60 years with first diagnosis of early-stage unfavorable HL to receive either fully concomitant (4xN-AVD; group A) or sequential (4xN, 2xN-AVD, 2xAVD; group B) nivolumab-based 1st-line treatment, each followed by 30Gy involved-site radiotherapy (IS-RT). The primary and final analyses showed excellent efficacy and an acceptable safety profile after 1- and 3-years of follow up; details were previously published (Bröckelmann et al. JAMA Oncol 2020 &amp; JCO 2023). Patients providing separate informed consent reported QoL and Fatigue by the EORTC QLQC30 questionnaire in addition to key sociodemographic data including employment status at baseline and after systemic treatment, radiotherapy and 1- and 3-years of follow-up (FU), respectively. Data were analyzed descriptively and time-to-recovery (TTR) calculated for resolution of fatigue (TTR-F, event defined as first documentation of a fatigue score &amp;lt;30 after end-of-treatment (EOT)) and return to work (TTR-W, event defined as first documentation of employment after EOT). Results: A total of 99 patients provided a median of 4 questionnaires per patient (range 1-11), with the vast majority (85%) providing baseline and at least one questionnaire during FU. Mean fatigue score was 22 points higher (95% confidence interval, CI 16.1-27.9) than the age- and sex-matched German reference population at baseline, worsened during treatment (+38.2, 95%CI 31.4-44.9) but improved over the course of FU (1-year +10.2, 95%CI 3.7-16.6) to normal values at 3-year FU (-3.4, 95%CI -10.7 to 3.9), without any differences between treatment groups. Similar trajectories were observed for global health status/QoL as well as the different functional and symptom scales. While improvement beyond baseline (79.6, 95%CI 76.5-82.7) was observed, global health status/QoL did not improve to age- and sex-matched reference values at 1- (87.2, 95%CI 83.2-91.2) and 3-year FU (92, 95%CI 87.8-96.2). Multiple regression analysis showed a significant effect of baseline score (ß 0.28-0.56) and age (ß 0.23-0.34) but not sex (p&amp;gt;0.2 each) on cognitive, emotional and social functional scales as well as fatigue at 1-year of FU. At 3-years of FU the effect of age remained significant (ß 0.48-0.66) for all functional or symptom scales except resolution of dyspnea, while baseline scores had no significant effect. More detailed analysis of the different QLQ-C30 scales is ongoing and will be presented at the meeting. Median TTR-F and TTR-W were 12.8 (95%CI 7.3-20.3) and 3.8 months (95%CI 1.4-8.0) after EOT, respectively. Cox regression analysis for TTR-F showed significant effect of baseline fatigue (HR 0.99, p=0.03) but not sex (HR 1.71, p=0.09) or age (HR 0.98, p=0.14). For TTR-W, Cox regression did not show significant effects of baseline fatigue (HR 1, p=0.93) or age (HR 0.99, p=0.69) but a trend for faster return to work in male patients (HR 1.82, p=0.06). Conclusion: This first ever analysis of PROs after anti-PD1 based first-line HL treatment with N-AVD indicates substantial improvement of functional and symptom scales as well as global health status/QoL at last FU compared to baseline. Baseline status and age have a significant effect for improvement of functioning and symptoms at 1-year of FU. Importantly, while substantial fatigue is present at baseline, relevant improvement with resolution to age- and sex-matched reference values is observed and recovery is influenced by baseline fatigue score.

Progression-Free Survival (PFS) and Toxicity with Nivolumab-AVD Compared to Brentuximab Vedotin-AVD in Pediatric Advanced Stage (AS) Classic Hodgkin Lymphoma (cHL), Results of SWOG S1826

Background: Approaches to therapy in pediatric and adult cHL have differed historically. Brentuximab vedotin (BV) is efficacious in pediatric patients (pts) with high-risk cHL when combined with chemotherapy and response based involved site radiation therapy (RT) ( Castellino. NEJM 2022). Inhibition of the PD-1 pathway, central to the pathogenesis of cHL, is safe and effective in children with relapsed HL but has not been evaluated in the frontline setting. Led by SWOG, the National Clinical Trials Network (NCTN) conducted the randomized, phase 3 trial S1826 to evaluate nivolumab (N)-AVD vs BV-AVD in pts ages ≥12 years (y) with newly diagnosed Stage 3-4 cHL. Methods: Eligible pts were randomized 1:1 to either 6 cycles of N-AVD or BV-AVD. At randomization enrollment was stratified by age, International Prognostic Score (IPS), and intent to use RT. Treating site of pts 12-17y, the subject of this subgroup analysis, declared intent to use RT for residual metabolically active lesions on the end of treatment PET per protocol. Recipients of BV-AVD were required to receive G-CSF prophylaxis vs optional with N-AVD. Dexrazoxane was permitted, but not mandated. Response and disease progression was assessed by investigators using the 2014 Lugano Classification. The primary endpoint was PFS; secondary endpoints included overall survival (OS), event-free survival (EFS), and safety. Results: Of 976 eligible pts enrolled (from 7/9/2019 to 10/5/2022): 24.3% (n=237) were 12-17 y and randomized to N-AVD (n=120) or BV-AVD (n=117). Median age was 15.6 y (range, 12-17.9 y), 50% of pts were male, 69% were white, 15% were black, and 18% were Hispanic. 27% had an IPS score 4-7. At the 2nd interim analysis (50% of total PFS events) the SWOG Data and Safety Monitoring Committee recommended reporting the primary results as the primary PFS endpoint crossed the protocol-specified conservative statistical boundary for the full trial. In the pediatric cohort, 6 PFS events were observed after N-AVD compared to 12 events after BV-AVD. At a median follow-up of 12.1 months, the PFS was compared between arms [HR 0.48, 95% CI 0.18-1.28, stratified one-sided logrank p=0.067) in the pediatric cohort; 1 y PFS: N-AVD, 94%, BV-AVD, 88% (Fig.1). There have been no deaths in this age group. Overall use of RT was 0.8% (2/237) and 79% of pediatric pts received dexrazoxane. The rate of grade (gr) ≥ 3 hematologic adverse events (AE) was 45% after N-AVD compared to 41% after BV-AVD, with 3% gr ≥ 3 febrile neutropenia and 1% with sepsis after either regimen, despite differences in GCSF use (59.2% N, 93.2% BV). Overall rates of immune related AEs (irAEs) (any gr) were low: pneumonitis (3.0% N vs 1% BV), and colitis (0% N vs 1% BV). Rash (any gr) was more common in BV-AVD (2% N vs 14% BV). Hypo/hyperthyroidism (any gr) was higher after N-AVD (2% N vs 0% BV). Rates of transaminitis were similar (ALT elevation: 42% N vs 54% BV). While sensory peripheral neuropathy was more frequent after BV-AVD (sensory: 18% N vs 29% BV; motor: 8% N vs 5% BV), only 1% was &amp;gt; grade 3. Discontinuation of N vs BV therapy occurred in 8.3% vs 2.6% of pediatric pts respectively, compared to 7.9% vs 21.1% of adults. Conclusions: In early follow-up, N-AVD and BV-AVD are well tolerated and associated with low rates of irAEs in pts ages 12-17 y. With 12.1 mos median follow-up the PFS benefit observed for N-AVD in pediatric pts mirrors that observed in the overall study. RT usage is lower, and cumulative doxorubicin dose is higher than historical pediatric cHL trials. The difference in rate of discontinuation between study arms and by age group needs further evaluation. Longer follow-up is needed to better define the roles of N-AVD and Bv-AVD for AS cHL. S1826 is a model NCTN trial, providing earlier access to novel agents and harmonization of treatment for adolescents and young adults with AS cHL. Funding: NIH/NCI/NCTN grants U10CA180888 and U10CA180819, U10CA180820, U10CA180821, U10CA180863, U10 CA180886; and Bristol-Myers Squibb. Bv provided by Seagen (Canada Only). Clinical Trial NCT03907488.

Pembrolizumab (pembro) in Children and Young Adults with High-Risk Classical Hodgkin Lymphoma (cHL) with Slow Early Response (SER) to Front-Line Chemotherapy (chemo): Updated Results from the Phase 2 Keynote-667 Study

Background: cHL is one of the most curable forms of childhood cancer, but patients (pts) who have a SER to initial chemo are at high risk of relapse. The approaches currently used to treat pts with SER, such as dose intensification and radiotherapy (RT), can cause long-term toxicity.An unmet need remains to optimize treatment in pts with cHL and SER while minimizing long-term toxicity. The open-label, phase 2 KEYNOTE-667 study (NCT03407144) is being conducted to evaluate the efficacy and safety of pembro plus chemo in pediatric pts with cHL and SER to front-line chemo. Early analysis of pts in KEYNOTE-667 with high-risk cHL showed that pembro plus cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) consolidation had manageable safety and promising antitumor activity, with 66% of pts being spared RT. We present updated results for pts with high-risk cHL and SER. Methods: Pts eligible for the high-risk group were 3-25 y old and had newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (&amp;lt;16 y old) or a Karnofsky score ≥50 (≥16 y old). All pts received 2 cycles of induction therapy with vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). After induction, response was assessed by PET/MRI/CT (early response assessment). Pts with rapid early response received nonstudy therapy. Pts with SER (Deauville score, 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) plus 4 cycles of COPDAC-28. Response was then assessed by PET/CT/MRI (late response assessment [LRA]). Pts with PET positivity at LRA (Deauville score, 4 or 5) received involved-site RT (28.8 Gy) to late PET-positive residua plus maintenance pembro Q3W for up to 17 cycles; pts with PET negativity received maintenance pembro Q3W for up to 17 cycles without RT. The primary end point was ORR by BICR per Cheson 2007 IWG criteria in pts with SER, determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included PET negativity after consolidation, EFS, OS, and safety. Results: This analysis included 62 pts with high-risk cHL and SER to frontline OEPA. The median time from enrollment to data cutoff (March 1, 2023) was 16.8 mo (range, 2.3-36.4). At the data cutoff, 34 pts (55%) had completed consolidation and maintenance therapy, 23 (37%) were ongoing on treatment, and 5 (8%) had discontinued because of adverse events (AEs; n = 1), progressive disease (n = 2), or withdrawal by pt (n = 2). Median age was 14 y (range, 5-22), 30 pts (48%) were male, 29 (47%) had bulky disease, and 41 (66%) had Ann Arbor stage IV disease. Pts had received a median of 17 administrations of pembro (range, 1-17); the median time on pembro was 11.0 mo (range, &amp;lt;0.1-11.8). Of 62 pts who received consolidation with pembro plus COPDAC-28, 53 (85%) had a LRA (9 are still in consolidation and have not reached the LRA time point), of whom 35 (66%) were PET negative by BICR (37 [70%] PET negative by investigator review). AEs regardless of causality that occurred during consolidation and maintenance were reported in 54 pts (87%), most commonly (≥15%) headache (n = 11; 18%), nausea (n = 11; 18%), cough (n = 10; 16%), COVID-19 (n = 10; 16%), and pyrexia (n = 10; 16%). Grade 3/4 AEs occurred in 21 pts (34%). 13 pts (21%) had a serious AE. No pts died because of AEs. Treatment-related AEs occurred in 38 pts (61%). Grade 3/4 treatment-related AEs occurred in 10 pts (16%). One pt (2%) discontinued treatment because of a treatment-related AE (grade 3 AST increased). Pembro-related AEs occurred in 23 (37%) pts; most commonly (≥5%) hypothyroidism (n = 4; 6%), nausea (n = 3; 5%), and ALT increased (n = 3; 5%). Three pts (5%) experienced grade 3/4 pembro-related AEs. One serious AE was related to pembro (abdominal pain). Six pts (10%) experienced immune-mediated AEs (hypothyroidism, n = 4 [2 grade 1, 2 grade 2]; colitis, n = 1 [grade 2]; pneumonitis, n = 1 [grade 2]). Conclusion: In this updated analysis, consolidation with pembro plus COPDAC-28 continued to have manageable safety and promising antitumor activity in pediatric pts with high-risk cHL and SER to front-line OEPA. Of pts with a LRA, 66% had a PET-negative response and were spared RT. These findings support the results of prior analyses and suggest that adding pembro to COPDAC-28 consolidation may augment responses in the high-risk cHL population.

Involved-Site Radiation Therapy Enables Effective Disease Control in Parenchymal Low-Grade Primary Cerebral Lymphoma

Involved-Site Radiation Therapy Enables Effective Disease Control in Parenchymal Low-Grade Primary Cerebral Lymphoma

Evolution of Radiation Fields from Involved Field to Involved Site—A Summary of the Current Guidelines by the International Lymphoma Radiation Oncology Group

Radiation therapy has been proven to be highly effective in the treatment of lymphoma. With increasing rates of long-term survival, the reduction in toxicity has gained importance. The evolving understanding of the diseases’ biology, as well as technical and conceptual advances, allows for a precise and individualized application of irradiation. Smaller treatment fields and safety margins make it possible to spare healthy neighbouring tissue (organs at risk). The International Lymphoma Radiation Oncology Group (ILROG) has developed several guidelines to optimize radiotherapy treatment in lymphoma patients. Since its introduction in 2013, involved site radiotherapy (ISRT) has been adopted as the standard of care in most treatment regimens in adult lymphoma. This article serves as a summary of the current ILROG guidelines, also considering contemporary developments and possible future directions.