Early-stage Hodgkin Lymphoma Research Articles

The evolving role of checkpoint inhibitors in the treatment of Hodgkin lymphoma

Since their initial approval as single agent therapy for multiply relapsed/refractory Hodgkin lymphoma (HL), the PD-1 inhibitors nivolumab and pembrolizumab have been incorporated into second-line salvage regimens, and they are being investigated in upfront therapy of newly diagnosed patients. As second-line therapy in combination with brentuximab vedotin or multi-agent chemotherapy, nivolumab and pembrolizumab provide high complete remission rates and durable progression-free survival after consolidative autologous stem cell transplant. Incorporation of these agents into frontline chemotherapy regimens is feasible, and early results from a Phase III trial of nivolumab-AVD compare favorably with the existing standard for advanced stage HL, brentuximab vedotin plus AVD. As nivolumab and pembrolizumab move into earlier lines of HL therapy, open research questions include the efficacy of checkpoint inhibitor regimens in patients who relapse after frontline exposure to nivolumab or pembrolizumab; the selection of patients with relapsed HL who can achieve durable remissions without autologous stem cell transplant; and the efficacy of the PD-1 inhibitors in the frontline therapy of patients with early stage Hodgkin lymphoma.

Fifteen-Year Experience of a Single Institution: Outcomes for Early-Stage Hodgkins Lymphoma Comparing Chemotherapy Alone Versus Combined Modality Therapy

Fifteen-Year Experience of a Single Institution: Outcomes for Early-Stage Hodgkins Lymphoma Comparing Chemotherapy Alone Versus Combined Modality Therapy

Toward a paradigm shift in prognostication and treatment of early-stage Hodgkin lymphoma.

Twenty years after the conceptual revolution that occurred in the millennium turnaround upon the introduction of PET/CT in lymphoma staging, restaging, and prognostication, a number of new parameters for PET reading have been proposed: (1) the shift from a qualitative to a semi-quantitative reading for PET reporting, (2) an international consensus on these novel interpretation keys, (3) a standardized and agreed procedure to measure the total metabolic tumour volume (TMTV), and (4) the proposition of new indexes to portray the tumour spread: (D-Max and Total Lesion Surface -TLS). These proved to be very powerful prognosticators, able to revolutionize the traditional Ann Arbor four-stage lymphoma staging. During the 17° Lugano meeting on lymphoma, one main question was asked to experts attending a closed workshop dedicated to new metrics for lymphoma diagnosis, staging, restaging, and prognostication: "Should the traditional 4-stage anatomic staging system be simplified to a more clinically relevant 2-stage system (e.g., limited vs. extensive disease)?" Early-stage HL is an example of how these new metrics could fit with this proposal.

How to treat localized Hodgkin lymphoma?

We aim to summarize the current knowledge on the management of early-stage classical Hodgkin lymphoma, with a focus on conventional strategies, incorporation of immunotherapies and exploration of novel prognostic markers. Long-term data on combined modalities (associating chemotherapy and radiotherapy) still supports their benefit in terms of progression free survival compared to chemotherapy alone in both early favourable and early unfavourable interim PET-negative classical Hodgkin Lymphoma. Novel agents, such as Brentuximab Vedotin and checkpoints inhibitors show promising and impressive results when added to first-line treatment. Various strategies have been used, mainly in phase 2 non randomized clinical trials. Interim PET-scan has limited prognostic value and its role in regimens incorporating immunotherapies is yet unknown. Other prognosis markers emerge, such as metabolic tumour volume and circulating tumour DNA. By reflecting tumour burden pretreatment and minimal residual disease on treatment, they might be useful tools guiding treatment decisions. Novel immunotherapy agents are likely to change the landscape in front-line management of classical early-stage Hodgkin lymphoma by combined modality treatment. Despite encouraging recent data, proof of their efficacy and safety on the longer term are still needed. Treatment decisions might be guided by new promising prognosis markers but their use in clinical practice is still to be determined.

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.

A Real-World Single-Center Study of Adult Hodgkin's Lymphoma

To summarize the clinical characteristics, therapeutic effect and prognostic factors of patients with Hodgkin's lymphoma (HL). A total of 129 patients with HL diagnosed in Peking University Third Hospital from January 2010 to March 2021 who were given at least one efficacy assessment after treatment were enrolled, and their clinical data, including sex, age, pathological type, Ann Arbor stage, ECOG score, blood test, β2-microglobulin, lactate dehydrogenase level, albumin level were collected. The clinical characteristics, therapeutic effect and long-term prognosis of the patients were summarized and analyzed. In classical HL, nodular sclerosis HL accounted for the highest proportion of 51.6%, followed by mixed cellularity HL (36.5%), lymphocyte-rich classical HL (3.2%), and lymphocyte depletion HL (0.7%), while nodular lymphocyte predominant HL accounted for 4.8%. The 3-year overall survival (OS) rate of HL patients was 89.8%, and 5-year OS was 85.0%. The 3-year progression-free survival (PFS) rate was 73.4%, and 5-year PFS was 63.1%. Multivariate regression analysis indicated that IPI score was an independent negative factor, while hemoglobin (Hb) level was an independent positive factor for OS in HL patients. When the mediastinal mass size was 9.2 cm, it was most significant to judge the survival status of HL patients. 5-year OS and 5-year PFS were 97.4% and 76.0% in early-stage HL patients without large mass, respectively, while in patients with advanced-stage HL was 83.4% and 55.9% (both P < 0.05). After 2-4 courses of treatment, the overall response rate (ORR) of patients who received chemotherapy combined with radiotherapy was 95.0%, while that was 89.6% in those with chemotherapy alone. The overall prognosis of patients with HL is satisfactory, especially those in early-stage without large mass. IPI score and Hb level are independent risk factors for the prognosis of HL patients. A 9.2 cm mediastinal mass can be used as the cut-off value for the prognosis of Chinese HL patients.

Estimation of Mediastinal Toxicities after Radiotherapy for Hodgkin Lymphoma-A Normal Tissue Complication Analysis of the HD16/17 Trial by the German Hodgkin Study Group.

Hodgkin lymphoma is a hematologic malignancy with excellent outcomes even in advanced stages. Consequently, the importance of treatment-associated toxicity increases. However, the exact estimation of individualized rates is difficult due to different disease extents, treatment strategies and techniques. The following analysis aims at a pre-treatment estimation of relevant mediastinal toxicities. Normal tissue complication probability calculations were used to evaluate the toxicity rates for the heart, lungs and female breast of patients undergoing radiotherapy for early-stage Hodgkin lymphoma. Overall, 45 Patients of the HD16 and HD17 trials by the German Hodgkin study group were included and risks were calculated using the Lyman-Kutcher-Burman model. The median values for pericarditis, pneumonitis and fibrosis of the left or right breast were 0.0%, 0.0%, 0.7% and 0.6% in the HD16 cohort, and 0.0%, 0.1%, 1.1% and 1.0% in the HD17 cohort, respectively. Correspondingly, none of the included patients displayed any of the evaluated toxicities during clinical follow-up. The use of higher doses (30 Gy) in the HD17 cohort led to an increase in toxicity compared to the HD16 cohort (20 Gy). No significant influence of the planning target volume size or the radiation technique could be found in this study. Both the clinically observed and calculated toxicity rates corroborate the overall low-risk profile of radiotherapy for Hodgkin lymphoma. Further treatment individualization will be attempted in the future.

Novel therapeutics for Hodgkin\'s lymphoma

Hodgkins LymphomaHL) was first described by Thomas Hodgkin in 1832., is a malignant disorder, a rare B cell lymphoma (mutant lymphocytes) with reasonable outcome due to the fair cure rates achieved by modern chemotherapy and/or radiotherapy. The incidence of HL is 2.6 cases per 100,000 people, accounts for 10% lymphoma cases. The Epstein–Barr virus (EBV) is detected in nearly 45% of HL patients Most of the affected patients are between ages 20 to 40 years. HL is uncommon in children &amp;#60; 5 years of age. The Reed-Sternberg (RS), large cells 50 micrometers in diameter which secrete cytokines to recruit reactive cells that include IL-5 and transforming growth factor-beta (TGF-beta). The RS cells are positive for CD 30 and CD15 &amp; sometimes for CD 20. They are negative for CD 45. The 5-year overall survival (OS) in stage 1 or stage IIa is approximately 90%;, the stage 4 disease has a 5-year OS of approximately 60%. More than 80 percent of all patients diagnosed with Hodgkin lymphoma can be cured by current treatment approaches. The cure rate is higher, approaching 90 percent, in younger patients and those with early-stage Hodgkins lymphoma (ESHL). Pragmatic therapeutic approach includes brief chemotherapy (ABVD- Adriamycin), bleomycin, vinblastine sulfate, and dacarbazine. For 3–4 cycles), For advanced-stage classic (CD30-positive) Hodgkin lymphoma, the combination of doxorubicin, vinblastine, dacarbazine, and brentuximab has emerged as a more effective, Patients with recurrent Hodgkin lymphoma would require high-dose chemotherapy followed by ASCT. Hodgkin lymphoma that recurs after ASCT would be managed by the checkpoint inhibitors nivolumab and pembrolizumab. Radiotherapy plays a role as a single modality in early stage lymphocyte-predominant HL. The role of autologous transplant was established decades ago by two randomized controlled trials demonstrating an improvement in PFS but not OS in patients with relapsed/refractory HL.

Management of limited-stage Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a rare type of B-cell malignancy with bimodal age distribution targeting young adults and elderly. Prognostic models are available to identify risk of recurrence and response to treatment. Currently, positron emission tomography scanning is most useful in optimizing therapy. Outcomes are generally excellent with standard chemotherapy or combined modality therapy. Balancing efficacy and the risk of late effects in Hodgkin lymphoma is essential, including early detection of potential complications. Incorporation of novel therapies such as brentuximab vedotin and checkpoint inhibitors are being explored in the frontline setting, having already demonstrated improved survival and tolerable toxicity in advanced HL. Furthermore, the addition of these agents have the potential to transform treatment paradigms for early-stage HL and may result in improved outcomes with decreased risks of late toxicities that continue to afflict long-term survivors. However, the patient population, sequencing, and combinations with cytotoxic chemotherapy all remain still standing questions as results of current and upcoming randomized trials are awaited. In this article, we discuss the current data on the approach to initial treatment of early-stage classical HL, review toxicity profiles, and examine upcoming novel therapy trials.

Development and Validation of the Early-Stage Hodgkin Lymphoma (HL) International Prognostication Index (E-HIPI): A Report from the Hodgkin Lymphoma International Study for Individual Care (HoLISTIC) Consortium

Background: There are a lack of clinical prediction tools in early-stage Hodgkin lymphoma (E-HL). We developed and validated a modern-day model, known as E-HIPI, to predict progression-free survival (PFS) within the first 5 years (y) incorporating detailed individual patient (pt) data from international clinical trials and prospective registry data that were standardized, normalized &amp; harmonized as part of the HoLISTIC Consortium (www.hodgkinconsortium.org). Methods: Model development utilized Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines (Moons, Ann Intern Med 2015) on a cohort of 3,080 newly-diagnosed E-HL pts treated on 4 seminal phase 3 clinical trials (NCIC: Meyer, NEJM 2012; RAPID: Radford, NEJM 2015; EORTC-GELA H9U: Ferme, E ur J Cancer 2017; EORTC/LYSA/FIL H10: Andre, JCO 2017). External validation was done in an independent cohort of 462 E-HL pts from a large registry (Princess Margaret, Toronto). Pts with classic HL, stage I or II disease, and ages 18-65 y were included. The primary outcome was PFS. Cox models were utilized with follow-up truncated at 5 years. Baseline predictors were: sex, stage, B symptoms, histology, number &amp; location of nodal sites, and continuous data values of age, maximum tumor diameter (MTD), white blood cell count (WBC), lymphocyte count, hemoglobin, albumin &amp; erythrocyte sedimentation rate (ESR). Multiple imputation was used for missing data. To consider possible non-linear relationships for continuous variables we examined plots &amp; cubic splines. We used backward elimination ( P&amp;lt;0.1) to develop the models &amp; internal validation with 200 bootstrap samples was conducted to estimate optimism &amp; correct for overfitting. The final prediction equations applied optimism corrections to beta coefficients &amp; hazard ratios (HR). Sensitivity analyses included model results stratified by PET staging (vs CT) and each HL trial. The models were evaluated in the external validation cohort &amp; compared using c-statistics. Model scores were also grouped by tertiles for visualization in Kaplan-Meier (KM) curves. Results: Median age in the development cohort was 35y; 51% were female; 81% had nodular sclerosis &amp; 77% stage II disease; 26% had B symptoms; 32% had mediastinal bulk (≥10cm or &amp;gt;1/3 diameter) and the mean MTD was 6.4 cm (interquartile range (IQR), 3.9-8.2). Median follow-up was 60 months (IQR 45-75). KM estimates at 5y was 90.7% (264 events) for PFS, and 97.1% (78 events) for overall survival (OS). After backward elimination, significant variables retained were age, sex, nodal location (cervical region), MTD &amp; albumin. Stage, ESR, or the number of nodal sites were not significant. Age was modeled with piecewise linear splines due to its non-linear relationship. See the Table for the final prediction model and optimism-corrected HRs. Optimism-corrected c-statistics in the development model was 0.63. Sensitivity analyses of stratification by type of imaging at staging or by each clinical trial demonstrated no change in model parameters or c-statistics. Most baseline characteristics and outcomes of the external validation cohort were similar besides median follow-up time (74 months, IQR 37-129). C-statistics for the E-HIPI model in external validation was 0.63. In addition, observed 5y outcomes stratified by tertile of predicted risk in the external cohort separated pts into a low &amp; higher-risk group, which comprised 1/3 &amp; 2/3 of pts, respectively ( Figure). Finally, model diagnostics revealed the potential for time dependency in the retained covariates. Further assessment of differential prediction between early (&amp;lt;2y) vs. later (2-5y) PFS events is ongoing. Conclusion: Following TRIPOD methodology, we rigorously developed and externally validated the E-HIPI among &amp;gt;3,500 E-HL pts.Discrete risk groups were delineated, and we identified several novel factors, including nodal location, sex &amp; key continuous variables that predict 5y PFS. Additional model refinement is underway, including formal calibration &amp; external validation via other HL registries (Stanford, Mayo/Iowa SPORE). A web-based calculator to simplify application of the E-HIPI will also be presented at ASH. Future planned modeling includes integration of differing treatments &amp; response-adapted imaging via multistate modeling to enrich individualized survival estimates and simulation modeling to predict late consequences.

Hodgkin Lymphoma - Mitigating Toxicity While Preserving Cure - Eight Year Data from MIOT International, Chennai, India

Background One of the most treatable cancers, Hodgkin's lymphoma (HL), has a 5-year survival rate of approximately 85%.We still see relapse and refractoriness in a tiny percentage of patients despite the fact that our disease is largely curable, and we also have additional issues including secondary neoplasia and long-term consequences on the heart. Our Hodgkin lymphoma statistics from 2011 to 2019 have been given in this paper. Methodology Between 2011 and 2019, data on patients with newly diagnosed classical HL (CHL) who received treatment were gathered. Analysis was done on the presenting characteristics, IPS risk classification, treatment procedures, treatment response, and 3-year outcome data. Results At presentation, there were 97 patients with newly diagnosed CHL, with a median age of 24 years (range, 11-72). The ratio of men to women was 1.62:1. Mixed cellularity, lymphocyte-rich, and lymphocyte-depleted CHL (LD, CHL) were histological subtypes that were present in 80.40%, 12.40%, and 7.20% of cases, respectively. At presentation, 52% of patients had advanced illness, and 80% had B symptoms. The Hodgkin IPI score was high in 58% of individuals with advanced stages. ABVD was given as the first line of therapy to 92% of patients. According to interim PET-CT scan findings, around 7 advanced stage Hodgkin patients were started with EscBEACOPP and then switched to ABVD prior to 2017. The front line treatment's overall response rate was 94.8%. Complete response rates for early-stage favourable and unfavourable risk groups were 94% and 86%, respectively, whereas they were 81% and 67% for advanced-stage low- and high-risk groups. The median duration of event free survival was 36 months. The 3-year EFS showed a significant difference between the early- and advanced-stage diseases, 93% and 81%, respectively (p 0.04). Relapse was found in eight patients, all of whom had BEAM Autograft post platinum based salvage treatment. Following interim PET negativity, we discontinued Bleomycin according to RATHL protocol. Three of our patients had bleomycin lung injury. Three patients had post-autograft recurrence, one of whom passed away due to a subsequent non-Hodgkin lymphoma. With the Brentuximab Bendamustine regimen, two patients were successfully salvaged and they had Haplo-identical transplant as third line salvage. Conclusions In early and late stage Hodgkin lymphoma, the three year EFS of 93% and 81% is equivalent to most western literature. In light of our little experience with Indian patients, the effect of Brentuximab is overwhelmingly favorable. At our facility, post-Autograft Brentuximab maintenance is being tested. There is no information on how Nivolumab will be useful in our context. Although there is little evidence to draw a conclusion that is statistically significant, frontline ABVD protocol treatment across risk categories and discontinuing Bleomycin after interim PET negative are helpful in our patients to enhance prognosis and decrease toxicity. Reference: Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma N Engl J Med 2016; 374:2419-2429 DOI: 10.1056/NEJMoa1510093Mohty, R., Dulery, R., Bazarbachi, A.H. et al. Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies. Blood Cancer J. 11, 126 (2021). https://doi.org/10.1038/s41408-021-00518-z

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.

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) &amp;gt;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.

Assessing out-of-pocket cost differences in treatment for Medicare-eligible patients with favorable prognosis early-stage Hodgkin lymphoma.

15 Background: In the treatment of favorable Hodgkin Lymphoma (HL), Level 1 evidence comparing combined modality therapy (CMT) with chemotherapy alone has persistently demonstrated that obviating radiation therapy (RT) worsens recurrence rates despite no significant overall survival difference. As there remains limited evidence on the granularity of the impact of insurance on HL treatment, this project disaggregates costs by insurance plans to enhance the transparency of out-of-pocket (OOP) cost estimations in Medicaid and/or Medicare-eligible (age 65+) patients. Methods: National Comprehensive Cancer Network guidelines were queried to assess the appropriate therapy for HL. Following initial adriamycin/bleomycin/vinblastine/dacarbazine (ABVD) chemotherapy x 2 cycles with Deauville 1-2 response on PET scan, CMT was defined as involved site RT (20 Gy / 10 fractions), while chemotherapy alone was defined as an additional ABVD x 2. Current Procedural Terminology and Healthcare Common Procedure Coding System codes identified treatments. OOP expenditures, deductibles, and copay/coinsurance were computed for Medicaid, Original Medicare, and Medigap Plan G plans via medicare.gov, medicaid.oh.gov, and cms.gov. Price estimates (from actual prices per insurance plan rather than claims data predictions) assume an Ohio hospital location (zip code = 44106) for all treatments. Total costs were calculated based on all treatments plus a 5-year follow-up (not adjusted for inflation). Treatment charges for chemotherapy alone include initial medical oncology office visit, cost of ABVD x 4, and infusion costs for 4 cycles. Additional treatment charges for CMT include initial radiation oncology consultation, treatment planning, dosimetry calculations, treatment device, simulation and verification, RT delivery, on-treatment visits, medical physics consultation, and annual TSH labs. Results: With Original Medicare plans, patients are faced with an OOP cost of 20% for Medicare Part B claims with no cost cap for approved procedures after the deductible. As such, patients are faced with a total 6-year charge of $1,928.95 for chemotherapy alone, and $2,385.28 for CMT. Under Medigap Plan G, patients encounter an OOP charge of $1,151.14 for chemotherapy alone and $1,176.34 for CMT. Medicaid beneficiaries (assuming all treatments are approved by Medicaid) face no OOP expenses for both treatment plans, as all expenses are covered without limit. Conclusions: By comparing OOP costs between Medicare and Medicaid plans, this model improves cost transparency in the treatment of favorable early-stage HL. Our findings indicate that omitting RT in favor of chemotherapy alone yields a cost savings of 2-24% at a 5-year follow-up. Further studies are required to assess whether these savings compensate for the inferior outcomes achieved by omitting RT in this patient population.

Prognostic Factors and Outcomes of Early-Stage Hodgkin's Lymphoma: Multi-Institutional Data From South India.

The online version contains supplementary material available at 10.1007/s12288-023-01692-9.

THE LOW‐RISK EARLY‐STAGE HODGKIN LYMPHOMA PATIENTS WITH INADEQUATE RESPONSE TO CHEMOTHERAPY. THE PRELIMINARY EXPERIENCE FROM THE RAFTING TRIAL

Introduction: Early-stage Hodgkin Lymphoma (eHL) treated with a combined modality approach (CMT): chemotherapy (CT) and radiotherapy (RT) is a highly curable disease. However, for 70% of eHL patients (pts.) CT alone might be sufficient for cure. The RAFTING trial is a phase 2, multicenter, international prospective study investigating risk-adapted treatment strategy in eHL pts. We hypothesized that CT alone will be sufficient for to cure low-risk pts. Here we would like to present the clinical characteristics of low-risk pts. for whom CT was not sufficient to achieve a complete response (CR). Methods: Treatment intensity in RAFTING is tailored to two risk categories: low or high risk. Low-risk pts. are defined by low baseline metabolic tumor volume (MTV) and negative interim PET after 2 ABVD cycles. High-risk pts. were defined by high baseline MTV and/or positive iPET2. Within the low-risk group the pts. without any risk factors according to modified EORTC (mEORTC) criteria (largest nodal mass (LNM) 5–10 cm, Age > 50 yo, ESR > 50 mm/h, ≥4 nodal areas (NA)) (group 1a) are treated with 2 ABVD cycles only whereas pts. with at least 1 risk factor (group 1b)—with 4 ABVD cycles. High-risk pts. (group 3) receive “triple” therapy (4 ABVD cycles, RT and nivolumab for 12 months; RT-NIV). In case of “limited relapse” (i.e., within initially involved lymph nodes and/or up to 3 new nodal areas) pts. receive delayed RT-NIV. Results: In a per-protocol analysis, out of 77 stratified pts. in March 2023, seven pts. (9%) with low-risk disease, had inadequate response to ABVD alone (defined as achievement less than CR or early relapse (<6 months after the end of the CT): 2 pts. from group 1a and 5 pts. from group 1b. Specifically, one pt. from Group 1a had an extended and symptomatic (B symptoms) relapse, and underwent salvage therapy with ASCT and two pts. from group 1b were withdrawn due to PI decision. While 4 pts. (1 in Group 1a and 3 in Group 1b) with less than CR (2 pts.) or early relapse (2 pts.) received RT + NIV. The most frequent risk factor among 1b pts. was LNM, which was observed in 4 pts., age >50 yo—in 2 patients, and ≥4 NA—in 1 pt. More than 1 risk factor had 2 pts. In 4 cases the confirmatory biopsy was done and was positive for HL in 3 out of 4 cases. Conclusion: The frequency of inadequate response after CT alone observed in the RAFTING trial was similar to that reported by the literature. The most frequent adverse prognostic factor presented in these small pts. subset was a LNM. Keywords: combination therapies, Hodgkin lymphoma, radiation therapy No conflicts of interests pertinent to the abstract.

Baseline‐PET derived metrics are the most relevant factors for risk stratification in early‐stage nonbulky HL: preliminary results of the RAFTING trial

Introduction: The efficacy of combined-modality treatment (Tx) with chemotherapy (CT) and radiotherapy (RT) in early-stage Hodgkin Lymphoma (eHL) is offset by long-term morbidity, with a cumulative incidence of 2nd primary malignancy at 40 years of 48.5% (Schaapveld 2015). The RAFTING trial (NCT Id. 04866654) is a phase-2 prospective single-cohort international study to explore the effectiveness of a risk-adapted Tx in non-bulky stage I-IIA eHL, based on the risk of CT failure (TxF) in a single-patient (p.) basis and in a personalized medicine design. Methods: p. are first stratified in 3 classes of TxF risk, depending on (a) modified EORTC criteria (m-EORTC), in which bulky is replaced by a Large Nodal Mass (LNM), defined by a longest ∅ measuring ≥5 cm in CT or PET/CT, (b) Metabolic Tumor Volume (MTV), with a SUVmax threshold method of 41% and cutoff value of 84 ml, and (c) PET-2 result (5-point scale). Tx stratification: Group 1: PET-2 neg. & low MTV p., treated either with 2 (group 1a) or 4 (group 2b) ABVD depending on no or ≥1 m-EORTC criterion presence, addressed, once in CR, to a 3-monthly cell-free tumor DNA (ctDNA) assay (CAPPSeq. Method, Spina 2018); Group 2: group 1 p. with < CR after ABVD or in “limited” relapse (LR), defined by eHL relapse in old and up to 3 new nodal areas, addressed to Involved-Node RT (INRT) and Nivolumab (N), 240 mg. i.v. twice a month for 24 doses; Group 3: PET-2+ and/or high MTV p., treated with the triplet ABVD × 4, INRT, 20 or 30 Gy (A-RxT-N). All PET/CT scans are centrally reviewed by an expert panel. The trial primary endpoint is a 3-Y PFS ≥90% in group 1 p. The secondary endpoints are: (a) Effectiveness of RxT (36 Gy) and N (same schedule of Group 3), in rescue p. with LR (b) effectiveness of the triplet A-RxT-N in high-risk (Group 3) eHL; (c) predictive value of ctDNA in detecting an impending eHL relapse after CT alone. Results: Preliminary results of risk stratification upon enrolment of the first 104/180 (58%) of the pre-planned sample size: in a per-protocol analysis, 88/104 (85%) turned out eligible and 73 stratified for risk. Non-eligibility reasons were higher HL stage, or bulky (10 p.) and early Tx stop, for p./investigator decision: (6p.). Out of 73 p. stratified, 53 (73%) were low-risk (Group 1), and 20 (27%) high risk (Group 3). Out of 53 low-risk p., 16 were in Group 1a: one of them was addressed to salvage Tx with ASCT because of an extended relapse 3 months after CT end. As many as 37 (70%) of low-risk p. belonged to Group 1b, mostly because of the presence of a LNM; two of them had a LR (entering Group 2) and started RxT-N rescue. Twenty p. (27%) had high-risk disease, most (14) for a high MTV, and a minority (6) for a positive PET-2. Updated results will be presented. The research was funded by: Polish Medical Agency ABM Ongoing Trial Keywords: Liquid biopsy, Ongoing Trials, PET-CT No conflicts of interests pertinent to the abstract.

Unfavorable early-stage Hodgkin lymphoma: assessment of patient characteristics in a real-world setting.

Aim: Unfavorable prognostic factors among classical Hodgkin lymphoma (cHL) patients in the real-world setting have yet to be fully characterized. Methods: In this retrospective study using the ConcertAI Oncology Dataset, patient characteristics, unfavorable prognostic factorsand treatment patterns were evaluated among patients diagnosed with cHL. Results: Among 324 adult cHL patients diagnosed 2016-2021, 16.1% were classified as early favorable, 32.7% early unfavorableand 51.2% advanced disease. Early unfavorable patients were younger and had a larger nodal mass. The prognostic factor B symptoms was most frequently documented in early unfavorable patients (59.4%), followed by bulky disease (46.2%), >3 involved lymph node regions (31.1%), and erythrocyte sedimentation rate ≥50 (25.5%). Conclusion: In this analysis of real-world data, we found that nearly a third of newly diagnosed cHL patients had early unfavorable disease. Our analysis also showed differences in the proportion of patients for each unfavorable factor among patients with early-stage unfavorable cHL.

A Quality Control Study on Involved Node Radiation Therapy in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 Trial on Stages I and II Hodgkin Lymphoma: Lessons Learned

Involved node radiation therapy (INRT) was introduced in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 trial, a large multicenter trial in early-stage Hodgkin Lymphoma. The present study aimed to evaluate the quality of INRT in this trial. A retrospective, descriptive study was initiated to evaluate INRT in a representative sample encompassing approximately 10% of all irradiated patients in the H10 trial. Sampling was stratified by academic group, year of treatment, size of the treatment center, and treatment arm, and it was done proportional to the size of the strata. The sample was completed for all patients with known recurrences to enable future research on relapse patterns. Radiation therapy principle, target volume delineation and coverage, and applied technique and dose were evaluated using the EORTC Radiation Therapy Quality Assurance platform. Each case was reviewed by 2 reviewers and, in case of disagreement also by an adjudicator for a consensus evaluation. Data were retrieved for 66 of 1294 irradiated patients (5.1%). Data collection and analysis were hampered more than anticipated by changes in archiving of diagnostic imaging and treatment planning systems during the running period of the trial. A review could be performed on 61 patients. The INRT principle was applied in 86.6%. Overall, 88.5% of cases were treated according to protocol. Unacceptable variations were predominately due to geographic misses of the target volume delineations. The rate of unacceptable variations decreased during trial recruitment. The principle of INRT was applied in most of the reviewed patients. Almost 90% of the evaluated patients were treated according to the protocol. The present results should, however, be interpreted with caution because the number of patients evaluated was limited. Individual case reviews should be done in a prospective fashion in future trials. Radiation therapy Quality Assurance tailored to the clinical trial objectives is strongly recommended.