Advanced-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.

External validation and calibration of the HoLISTIC Consortium's advanced-stage Hodgkin lymphoma international prognostic index (A-HIPI) in the Brazilian Hodgkin lymphoma registry.

The Hodgkin lymphoma International Study for Individual Care (HoLISTIC) Consortium's A-HIPI model, developed in 2022 for advanced-stage classical Hodgkin lymphoma (cHL), predicts survival within 5 years amongst newly diagnosed patients. This study validates its performance in the Brazilian Hodgkin lymphoma registry. By 2022, the Brazilian HL registry included 1357 cHL patients, with a median 5-year follow-up. Probabilities for 5-year progression-free survival (PFS) and overall survival (OS) were calculated using A-HIPI-model equations. Discrimination (Harrell C-statistic/Uno C-statistic) and calibration measures assessed external validation and calibration. Lab values beyond the allowed range were excluded, mirroring the initial A-HIPI analysis. A total of 694 advanced-stage cHL patients met the original inclusion criteria (age 18-65 years, Stage IIB-IV). Median age was 31 years; 46.3% were females. Stage distribution was IIB (33.1%), III (27.4%), IV (39.5%). Bulky disease in 32.6%. Five-year PFS and OS were 68.4% and 86.0%, respectively. Harrell C-statistics were 0.60 for PFS and 0.69 for OS, and Uno C-statistics were 0.63 for PFS and 0.72 for OS. Calibration plots demonstrated well-calibrated predictions with calibration slopes of 0.91 and 1.03 for 5-year OS and PFS, respectively. Despite differing patient, clinical characteristics, and socioeconomic factors, the baseline prediction tool performed well in the Brazilian cohort, demonstrating adequate discrimination and calibration. This supports its reliability in diverse settings.

A new scoring system to predict survival in elderly advanced stage Hodgkin lymphoma patients

Predictive prognostic scoring (PS) systems are not primarily applicable to elderly patients with classical Hodgkin lymphoma (cHL). The objective of this study was to develop a PS system for these patients. The derivation cohort (DC) was utilized for model development, consisting of 97 variables. The resulting algorithm was named as Hodgkin’s Lymphoma Early Death in the Elderly within 12 months (HEDEL12). Internal and external validation cohorts (IVC and EVC) were employed for validation. A total of 286 patients were evaluated retrospectively. In DC 38 of 178 patients died within the first 12 months and overall survival (OS) at 12-month was 78.6%. Independent predictors of HEDEL12 were female sex, low albumin levels (<3.5 g/dL), and ECOG scores 2-4. According to HEDEL12 scores 0–1, OS at 12- months were 89.8% and 91.0% for IVC and EVC, respectively. The HEDEL12 scoring is useful in predicting the survival of advanced-stage cHL patients.

Efficacy of escalating therapy with brentuximab vedotin-AVD in advanced stage Hodgkin lymphoma patients with positive interim positron emission tomography after ABVD.

Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.

Efficacy and safety of standard BEACOPP regimen versus ABVD regimen for treatment of advanced Hodgkin's lymphoma.

The current treatment regimens for Hodgkin's lymphoma (HL) are associated with high incidences of adverse events. This study aimed to compare the efficacy and safety of doxorubicin + bleomycin + vincristine + dacarbazine (ABVD) and standard bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (BEACOPP) chemotherapy in the treatment of advanced stage HL. This multicenter, randomized, parallel, open, positive control noninferiority trial was conducted from 2016 to 2019 and comprised 93 subjects who were randomized in a 1:1 ratio between the treatment (BEACOPP; n = 44) and control (ABVD; n = 49) groups. The primary efficacy endpoint of this trial was the objective response rate (ORR) after eight cycles of chemotherapy, which was 100.00% (36/36) in the treatment group and 95.74% (45/49) in the control group. The incidence of adverse reactions was 100% in both groups. Significant differences (P < 0.05) in the incidences of grade 3 (39/44 [88.64%] vs. 23/49 [46.94%]) and grade 4 (27/44 [61.36%] vs. 8/49 [16.94%]) adverse events were observed between the treatment and control groups, respectively. However, most of these reactions were manageable, with no serious consequences, and were reversible after discontinuation of the treatment. Both regimens had a similar ORR and were associated with a high number of adverse events. The ABVD regimen was better tolerated and safer than the standard BEACOPP regimen. This study indicates that the standard BEACOPP regimen may be considered as a treatment option for patients with advanced HL.

Treatment approaches for older Hodgkin lymphoma patients.

Hodgkin lymphoma (HL) occurs at two age peaks around 25 and 60 years of age. Due to varying fitness and co-morbidities older patients are a heterogeneous group that has relatively poor treatment outcomes. The evolving therapeutic landscape for older HL is summarized herein. Due to lack of data from larger trials and approval of novel drugs, first-line treatment of limited-stage HL (i.e. early-stage favourable and unfavourable) remains largely A(B)VD and radiotherapy based. For patients with advanced-stage HL, the anti-CD30 antibody-drug conjugate brentuximab vedotin is approved in combination with AVD chemotherapy (BV-AVD). Due to toxicities such as febrile neutropenia or polyneuropathy and lack of improvement in progression-free and overall survival in the older subgroup, fully concomitant BV-AVD is however not used widely. More recently, promising early data was reported with the combination of nivolumab and AVD (N-AVD) in patients >60 years with advanced-stage HL. Second-line treatment depends on fitness and might include high-dose chemotherapy and autologous stem-cell transplantation for selected patients. For unfit or multiply relapsed patients, anti-PD1 antibodies are the preferred treatment option. The increasing number of older HL patients constitutes a therapeutic challenge despite recent advances and the increased usage of targeted agents.

Treatment Strategies in Advanced-Stage Hodgkin Lymphoma.

The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the introduction of the international prognostic scoring (IPS) system; therapeutic decision-making based on both IPS and interim PET/CT data; the finding that a negative interim PET/CT result could be safely used for treatment de-escalation; the introduction of intensive combination chemotherapy like escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin (vincristine), procarbazine, and prednisone); and further modification of this protocol with the incorporation of a conjugated anti-CD30 antibody brentuximab vedotin (BV) into first-line regimens, like BV-AVD (BV+ adriamycin, vinblastine and dacarbazine) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). The accruing data about the toxicity of the escalated BEACOPP protocol have led to decreasing the number of therapeutic cycles, substitution of toxic agents like procarbazine with dacarbazine (e.g., BEACOPDac), and reduction/omission of radiation therapy. Lately, a significant advancement has been made by the integration of checkpoint inhibitors in the first-line treatment, with preliminary results demonstrating the superiority of anti-PD1 combined with chemotherapy (nivolumab-AVD) compared to the BV-AVD regimen. This review aims to analyze recently published studies whose findings could change the treatment practice in advanced-stage HL.

Current Standards in the Treatment of Hodgkin Lymphoma

This review discusses current trends in the treatment of Hodgkin lymphoma, focusing on optimizing therapy outcomes while minimizing toxicity. We summarize advances made by the incorporation of Brentuximab Vedotin into first line therapy for advanced stage Hodgkin lymphoma. Similarly, the incorporation of checkpoint-inhibition into first-line therapy holds great promise and early results suggest superior efficacy with reduced toxicity. In relapsed or refractory Hodgkin lymphoma, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation remains the standard approach. However, the remarkable efficacy of checkpoint inhibition in this setting has the potential to redefine treatment paradigms and obviate the need for HD-ASCT in select patients. Finally, we discuss the evolving landscape of nodular lymphocyte predominant Hodgkin lymphoma and reclassification to nodular lymphocyte predominant B-cell lymphoma, with increasing recognition of its distinct characteristics and treatment strategies.

Machine Learning-Based Survival Prediction Models for Progression-Free and Overall Survival in Advanced-Stage Hodgkin Lymphoma.

Patients diagnosed with advanced-stage Hodgkin lymphoma (aHL) have historically been risk-stratified using the International Prognostic Score (IPS). This study investigated if a machine learning (ML) approach could outperform existing models when it comes to predicting overall survival (OS) and progression-free survival (PFS). This study used patient data from the Danish National Lymphoma Register for model development (development cohort). The ML model was developed using stacking, which combines several predictive survival models (Cox proportional hazard, flexible parametric model, IPS, principal component, penalized regression) into a single model, and was compared with two versions of IPS (IPS-3 and IPS-7) and the newly developed aHL international prognostic index (A-HIPI). Internal model validation was performed using nested cross-validation, and external validation was performed using patient data from the Swedish Lymphoma Register and Cancer Registry of Norway (validation cohort). In total, 707 and 760 patients with aHL were included in the development and validation cohorts, respectively. Examining model performance for OS in the development cohort, the concordance index (C-index) for the ML model, IPS-7, IPS-3, and A-HIPI was found to be 0.789, 0.608, 0.650, and 0.768, respectively. The corresponding estimates in the validation cohort were 0.749, 0.700, 0.663, and 0.741. For PFS, the ML model achieved the highest C-index in both cohorts (0.665 in the development cohort and 0.691 in the validation cohort). The time-varying AUCs for both the ML model and the A-HIPI were consistently higher in both cohorts compared with the IPS models within the first 5 years after diagnosis. The new prognostic model for aHL on the basis of ML techniques demonstrated a substantial improvement compared with the IPS models, but yielded a limited improvement in predictive performance compared with the A-HIPI.

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.

Reduced Corticosteroid Exposure Is Safe and Does Not Reduce Disease Control among Hodgkin Lymphoma Patients Treated with Escalated BEACOPP (eBEACOPP).

Background and Objectives: eBEACOPP is the most effective chemotherapy regimen for younger patients with early unfavorable (EU) and advanced-stage (AS) Hodgkin lymphoma (HL), albeit with significant toxicities. The 14-day/cycle prednisone course contributes to side effects, including osteoarticular events like avascular bone necrosis (AVN). Our center has been using eBEACOPP since 2009 for AS and 2014 for EU patients. In 2016, we reduced prednisone treatment to 7-10 days to lessen AVN risk. We analyzed the effects of this approach. Materials and Methods: We retrospectively collected data on patients who received at least two cycles of eBEACOPP for first-line HL treatment. Results: A total of 162 patients (33 EU, 129 AS) were included. Their median age was 31 (range 19-59 years), and 88 were males. A total of 94 patients received full corticosteroid courses, and 68 received reduced corticosteroid courses. The overall response rate (ORR) was 98%. Different corticosteroid dosings had no significant effect on ORR, febrile neutropenia episodes, or hospital admissions. After a median follow-up (mFU) of 58 months, the 5yPFS for the entire cohort was 98% vs. 95% for the standard course vs. the short corticosteroids course, respectively (p = 0.37), while the 5yOS was 98% vs. 99% for the standard course vs. short corticosteroids course, respectively (p = 0.87). In AS patients intended to be treated with six eBEACOPP cycles, 5yPFS and 5yOS were 100% vs. 97% and 100% vs. 99% for standard vs. short corticosteroid courses, respectively (p = 0.56 and p = 0.17). In EU patients, 5yPFS was 97% (standard) vs. 95% (short) (p = 0.98) and 5yOS 100% vs. 93.3% (p = 0.87). Osteoarticular events were numerically lower in patients receiving the shorter prednisone course, both in the whole cohort and in the subgroup of patients treated with six cycles of eBEACOPP, but this difference failed to reach statistical significance. Conclusions: eBEACOPP provides excellent and durable first-line disease control. Shortening the corticosteroid course does not compromise efficacy, potentially reducing toxicity. However, longer follow-ups and larger studies are needed for confirmation.

Long-term clinical outcomes of combined modality therapy for advanced-stage Hodgkin lymphoma in the PET era: A retrospective study.

The role of consolidation radiation therapy (CRT) after complete metabolic response to chemotherapy in advanced-stage (stage III and IV) Hodgkin lymphoma (HL) is controversial. This study was undertaken to assess the clinical outcomes in terms of event free survival, local failure free survival and overall survival in individuals with advanced HL treated with chemotherapy and CRT. A retrospective review was conducted to study the long-term clinical outcomes in individuals diagnosed with HL and treated with chemotherapy and CRT from 2012 to 2016 at a tertiary cancer care hospital in India. Data from 203 study participants with advanced-stage HL were analyzed. Positron emission tomography-computed tomography (PET-CT) was done at baseline and after 2 cycles for response assessment. The median age at presentation was 32 yr [interquartile range (IQR): 26-46]. Early metabolic response (after 2 cycles) and delayed metabolic response (after 4 or 6 cycles) were observed in 74.4 and 25.6 per cent of individuals, respectively. With a median follow up of 52 months (IQR: 40-67), the five-year event-free survival (EFS), local failure-free survival (LFFS) and overall survival (OS) were 83.2, 95.1 and 94.6 per cent, respectively. On univariate analysis, extranodal disease was associated with inferior EFS (P=0.043). Haemoglobin <10.5 g/dl (P=0.002) and Hasenclever index >3 (P=0.00047) were associated with poorer OS. Relapses were observed in 28/203 (13.8%) study participants with predominance at central nodal stations. The median time to relapse was 19.4 months (IQR: 13-33). Local relapse alone (at the irradiated site) was observed in 5/28 study participants, systemic (distant) relapse in 14/28 individuals, while both systemic and local relapse was observed in 9/28 participants. Extranodal disease (P=0.05), bulky disease (P=0.005) and haemoglobin concentration ≤10.5 g/dl (P=0.036) were significant predictors for disease relapse. Individuals with advanced-stage HL treated with anthracycline-based chemotherapy (anthracycline-based chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine regimen) and CRT had excellent long-term outcomes. As isolated infield failures are uncommon, selective consolidation with conformal RT to high-risk sites improves final disease outcomes.

Clinical Features, Treatment Patterns and Outcomes of 864 Newly Diagnosed Hodgkin Lymphoma Patients in Latin America and the Impact of PET Scan Availability on Survival: A Study from the Grupo De Estudio Latinoamericano De Linfoproliferativos (GELL)

Background: Hodgkin lymphoma (HL) is a lymphoid neoplasm with high cure rates. Around 90% of patients (pts) will achieve response to first-line treatment. Real-world studies in Latin America (LATAM) are lacking. Moreover, inequity in the access to imaging technology and drugs represent a real challenge for Latin American countries with palpable influences in patient outcomes. Herein, we describe the clinical features, treatment patterns, and outcomes of HL pts managed in LATAM. Method: We conducted a retrospective cohort study of adults aged ≥17 years with newly diagnosed HL across academic centers in 7 LATAM countries from 2003 to 2022, with follow-up through July 2023. Medical records were manually reviewed, and data were abstracted in a standardized form. Cancer staging was performed by Ann Arbor and German HL Study Group criteria. Survival probabilities were estimated with the Kaplan-Meier method and compared with the Log-rank test. Multivariable Cox regression models were fitted by cancer stage stratification. A landmark analysis was performed to assess the lack of PET scan availability at the end of treatment (EOT) in LATAM. Results: Of 965 pts identified, 864 had sufficient data for analysis. Pts were young (56% &amp;lt;40 years; median 36 [17-88]) with slight male predominance (53%). 9 (3%) pts were HIV positive. Nodular sclerosing (62%) and mixed cellularity (22%) were the most common HL subtypes (p&amp;lt;0.01). Clinically, most pts had good performance status (ECOG≤1, 96%), no B symptoms (62%) and normal serum LDH (60%). Mediastinal presentation was seen in 14%, bulky mass (&amp;gt;10 cm) 23%, nodal involvement &amp;gt;3 sites 34% and extranodal involvement 25%. Advanced stage was common (57%); 22% and 21% had favorable and unfavorable limited stage HL, respectively. ABVD was the most common first-line regimen (96%); 8 pts received BEACOPP, and 1 BV-AVD. Radiation was utilized in 40% of limited and 21% of advanced stage HL. Only 63% and 48% had interim (iPET) and EOT PET scan, respectively. Most pts were managed at private than public institutions (59%, p&amp;lt;0.01). With a median follow up of 65 [59-71] months the 5-yr overall survival (OS) and progression-free survival (PFS) rates in all HL pts were 85% (82-88, 95% CI not reached, NR) and 64% (60-69, 95% CI NR), respectively. Better OS and PFS were seen in pts younger than 60 (p&amp;lt;0.01), ECOG≤1 (p&amp;lt;0.01) and limited stage HL (p&amp;lt;0.01). Overall response rate at the EOT assessed by either PET or CT scan was 89% (76% complete and 13% partial). In those assessed by iPET, results yielded 86% keeping same plan, 7% de-escalation and 3% escalation. In our cohort, 11% had refractory HL and 18% relapsed after achieving response. Given the inferior PFS to first-line seen in our LATAM HL pts compared to historical cohorts, we looked at possible factors associated to early relapse. Those assessed by PET at the EOT had significantly superior 5-yr PFS than those assessed by CT scan (PET vs CT: favorable HL 91 vs 71%; unfavorable 83 vs 35%; advanced 79 vs 51%) ( Figure). OS was inferior only in pts with unfavorable HL not assessed by PET (94 vs 76%, p=0.03). In the multivariable analysis, the lack of PET assessment at the EOT was associated with short PFS in unfavorable (aHR 7.81 [1.46-41.88], p=0.02) and advanced (aHR 17.35 [4.66-64.61], p&amp;lt;0.01), and a non-statistically significant worse PFSvin favorable HL (aHR 5.05 [0.56-45.72], p=0.15). Other factors associated to short PFS were extranodal disease (aHR 35.29 [5.62-209.07], p&amp;lt;0.01) in unfavorable, and high serum LDH (aHR 2.31 [1.2-4.46], p=0.01) in advanced HL. Interestingly, pts with advanced HL managed in public institution had less risk for relapse than those in private institutions (aHR 0.13 [0.03-0.51], p&amp;lt;0.01). Conclusion: To our knowledge, this is the largest cohort of newly diagnosed HL pts in LATAM in the real-world setting. We observed similar clinical features in LATAM HL pts than those previously reported. ABVD was widely utilized in LATAM, and the 5-yr OS of 85% in all pts aligns with international estimates. However, our findings underscore the impact of limited access to PET scan at the EOT in LATAM, leading to lower PFS outcomes compared to those reported in developed countries. Despite this challenge, salvage therapy seems to rescue our LATAM HL pts, thus, OS remains optimal. To improve outcomes and minimize late effects following treatment completion, increasing the use of PET-adapted therapy for managing adult pts with HL in LATAM should be prioritized.

External Validation of the Advanced-Stage Hodgkin Lymphoma International Prognostic Index (A-HIPI): Strong Calibration in the Brazilian Prospective Hodgkin Lymphoma Registry

Background: To be useful across the broadest range of patients and clinical settings, clinical prediction models should be externally validated in different data sets and clinical settings and refined over time. In 2022, the HoLISTIC Consortium (www.hodgkinconsortium.org) developed and validated the A-HIPI model via TRIPOD guidelines for adults 18-65 with advanced stage classic Hodgkin Lymphoma (AS-HL) (Rodday et al., JCO 2023). The A-HIPI model, based on individual patient (pt) data from more than 5000 patients (pts) from North America, Europe, and Australia, predicts progression-free survival and overall survival within the first 5 years (PFS5 and OS5) based on pre-treatment pt and disease characteristics (www.qxmd.com/calculate/calculator_869/a-hipi). In collaboration with Brazilian clinical experts and researchers, we describe the performance of the A-HIPI in the Brazilian Prospective HL registry. Methods: The Brazilian Prospective HL registry (NCT02589548) was originally established in 2009 with the goal of evaluating risk factors, treatment, and disease outcomes. By 2022, 1357 pts with classic HL were registered with a median follow-up of 5 years for surviving patients (Biasoli I. HemaSphere 2022). 5-year PFS and OS were calculated using the Kaplan-Meier method. Using the methodology for validation and calibration outlined in by Rodday et al., calculated risk scores were calculated for PFS5 and OS5. Harrell c-statistic and the Uno c-statistic were calculated to evaluate discrimination (i.e., differentiation of those at higher risk of having an event from those at lower risk) and plots of deciles of predicted vs. observed outcomes were created to assess calibration (i.e., how similar the predicted absolute risk of the model is to the true (observed) risk in an external cohort). In the primary A-HIPI analysis, laboratory values outside of permitted range were excluded and not imputed. This was checked in sensitivity analysis using multiple imputation for missing values; no substantial differences were noted. Thus, in the current validation, out-of-range lab values were excluded. There were no exclusions in the current analysis for early death, defined as deaths that occurred from the onset of first treatment until 30 days after its end. Pts with HIV were excluded from the assembled cohort. Results: 694 patients with AS-HL with the inclusion criteria of the original study were included in the present study. The median age was 30.9 years (range, 18-65) at diagnosis with 46% of the pts being female. 230 (33%) patients were classified as Stage IIB, 190 with Stage III (27.4%), and 274 (39.5%) with Stage IV. Bulky disease (&amp;gt;10 cm) was present in 226 patients (33%). Median hemoglobin was 11.6 g/dL (8-16.3), median albumin 3.63 g/dL (1.41-5.46), and median lymphocyte count was 1.5 x 10 3 µL (0.10-4.76). The 5-y PFS (PFS5) in the A-HIPI Brazilian validation dataset was 68.4% (95% CI: 64.7-71.9%) and the 5-y OS (OS5) was 86.0% (95% CI: 82.8-88.6).Harrell c-statistics for the A-HIPI model were 0.60 (95% CI, .56-.64) for 5-year PFS and 0.69 (95%CI, .64-.74) for 5-year OS and Uno c-statistics for the A-HIPI model were 0.63 (95% CI, .58-.68) for 5-year PFS and 0.72 (95%CI, .65-.78) for 5-year OS. Calibration plots (see figures) show the predicted A-HIPI model estimates were well calibrated with the observed outcomes in the Brazilian HL registry. Conclusions: Despite important differences between the original development cohort for A-HIPI and the Brazilian registry in patient and clinical characteristics (e.g., younger age at diagnosis, greater proportion of Stage IV disease) and the well characterized impact of income maldistribution and socio-economic status on clinical outcomes (Biasoli et al., Int J Cancer 2018), the A-HIPI clinical prediction tool performed well in the Brazilian Prospective Registry. This included evidence of adequate discrimination and calibration. Future studies are planned, including the impact of treatment selection and response, use of interim imaging, and supportive care may underscore important differences in outcomes among adults with AS-HL.

Bleomycin Affects Lung Function for at Least 5 Years after Treatment for Hodgkin Lymphoma - Data from the International, Randomised Phase 3 Rathl Trial

Introduction: Bleomycin has been an integral part of classical Hodgkin lymphoma (HL) treatment for decades but carries significant toxicity. In particular, acute bleomycin-related lung toxicity occurs in a minority of patients (pts) but has mortality rates as high as 25%. The long-term effects of bleomycin in HL and its impact on lung function are not well known and there is no established guidance for lung screening. The aim of this analysis was to evaluate the impact of bleomycin dose on lung function up to 5 years after treatment in pts recruited to the international, phase 3 RATHL trial. Methods: RATHL recruited pts with intermediate- or advanced-stage HL aged ≥18 years. Pts received 2 cycles of standard ABVD followed by PET assessment. Pts with complete metabolic response (CMR) received 4 further cycles of chemotherapy, with (ABVD arm; n=469) or without (AVD arm; n=464) bleomycin (12 or 4 doses bleomycin in total, respectively). PET-positive pts switched to BEACOPP-based treatment (total 8-10 doses bleomycin; n=172). Pulmonary function tests (PFTs) were performed at baseline, end of treatment (EOT) and annually for 5 years. Linear regression was used to assess changes in DLCO from baseline and Cox regression used to assess the time to return to within 10% of baseline values, censoring at relapse or death, in all pts, and those with a more than 10% reduction at EOT. Results: Median age was 33 years (range 18 - 79), 8.2% were aged &amp;gt;60 and 15.1% had a pre-existing respiratory disorder, including asthma in 8.4%. In pts with available data, 18.2% were smokers and 22.2% were ex-smokers with a median of 10 pack-years (IQR: 4 - 20). Baseline DLCO values were low (&amp;lt;75%) in 339 (29.8%) pts and were influenced by disease burden, with lower median DLCO in pts with mediastinal bulk (79%, IQR: 69.0 - 89.4) than in those without (83.1% (73- 94), p=0.006). Grade ≥3 respiratory adverse events occurred more frequently in the ABVD arm (17 events; 3.6%) than with AVD (7 events; 1.5%), p = 0.041. There was one respiratory death (pulmonary fibrosis) in the ABVD arm. PFT data were available for 779 pts at EOT, 386 pts at 2-year follow up and 196 pts at 5 years; uptake of repeat PFT was unaffected by treatment arm or presence of prior abnormal results. Changes in DLCO adjusted to baseline values for randomised patients are shown in the Figure. Pts randomised to AVD had a significantly smaller reduction in DLCO at EOT compared to those given ABVD or escalated to BEACOPP: +4.1% (95%CI: 1.8 to 6.5, p = 0.001 and +4.1 (0.1 to 8.0) p = 0.043). Other factors associated with a reduction in DLCO were age (-1.6% (-2.4 to -0.8) for a 10-year increase, p&amp;lt;0.001), female sex (-2.7% (-5.0 to -0.44), p=0.019) and baseline pulmonary disease (-4.9 (-8.4 to -1.4), p = 0.006). There was no evidence of an association with abnormal baseline DLCO values. DLCO had reduced to &amp;lt;90% of baseline values for 247 pts (59.8%) in the ABVD arm compared with 167 pts (40.6%; p&amp;lt;0.001) with AVD, and 63 (53.1%) with BEACOPP. At 2 years after EOT, DLCO had recovered to within 90% of baseline for 69.6% (95% CI: 64.9 - 74.1) of pts in the ABVD arm, 81.4% (77.4 - 85.2) with AVD and 68.5% (59.8 - 76.9) with BEACOPP. DLCO values remained &amp;lt;90% of baseline for 136 pts during follow-up with no reported recovery, with a median PFT follow-up of 18.3 months (IQR: 6.4 - 42.7) after registration. 58 pts had persistent reductions in DLCO at ≥2-year follow up (35 ABVD arm, 10 AVD; 13 BEACOPP arm). Factors associated with a slower recovery of DLCO on univariable analysis were treatment on the ABVD arm (HR 0.71, 95% CI: 0.57 - 0.90; p=0.004 compared with AVD), history of pulmonary disease (HR 0.66 (0.46 - 0.95; p=0.023) and female sex (HR 1.25, 1.01 - 1.54; p=0.041). DLCO values were consistently higher in the AVD arm than with ABVD throughout follow-up with a mean difference of 3.2% (95% CI: 0.3 to 6.1; p=0.029) at 2 years and 5.0% (1.20 to 8.8; p=0.010) at 5 years, after adjustment for baseline DLCO values (see Figure). Findings were consistent after excluding the minority of pts that received radiotherapy. Conclusions: Baseline RFTs are influenced by disease burden and do not predict subsequent bleomycin-related changes in lung function. Whilst individual grade ≥3 events were uncommon, there was a population-wide reduction in diffusion capacity that was only partially reversible at 5 years, findings that might have clinical consequences in later years for pts cured of HL. These data strongly support efforts to minimise bleomycin use in the treatment of HL.

Does discontinuing bleomycin due to toxicity increase the risk of lymphoma progression? Real-life data from a homogeneous population of advanced stage Hodgkin lymphoma

Hodgkin Lymphoma (HL) is often curable with ABVD therapy and improving outcomes is a main goal of ongoing research. Bleomycin-associated pneumonitis (BAPT) is a potentially life-threatening complication that necessitates bleomycin discontinuation. We conducted this study on a homogenous cohort of advanced stage HL treated only with ABVD for frontline therapy to assess if bleomycin discontinuation increases the risk of lymphoma progression. After the exclusion of patients who received radiotherapy or other drugs, 106 and 28 patients in the six-cycle ABVD and BAPT groups respectively had similar survival curves for progression and death with a 49-month median follow-up. PFS rates were also very similar at two and four years from diagnosis with 2-year PFS rates of 83.9% and 82.1% (RR = 1.1 95%CI = 0.45–2.2). Outcome comparisons were also similar between the two groups when stratified according to early response assessment with PET/CT. Patients who discontinued bleomycin due to toxicity did not experience an increased risk of progression compared to patients who completed six ABVD cycles.

The role of FDG-PET scanning and PET-adapted therapy in the primary treatment of Hodgkin lymphoma: A primer for clinicians

The evolving treatment paradigm for classical Hodgkin lymphoma (cHL) remains focused on maintaining high rates of progression-free survival (PFS) and overall survival (OS), while seeking to reduce both short-term and late toxicities from chemotherapy and radiation. Functional imaging with fluoro-deoxyglucose (FDG)‑positron emission tomography (PET) combined with computed tomography (CT) is recognized as standard for staging and response evaluation of Hodgkin lymphoma (HL). Recent randomized controlled trials evaluating FDG-PET-guided therapy for patients with limited stage and advanced stage Hodgkin lymphoma provide clinicians and patients with meaningful data upon which to base individualized treatment approaches. FDG‑PET scanning after two cycles of therapy (interim PET or PET2) represents the most important determinant of further appropriate treatment and subsequent outcomes, and is now the cornerstone of risk-adapted therapy for all patients receiving curative-intent initial therapy for Hodgkin lymphoma. For patients with limited stage cHL, post-chemotherapy assessment (after two or four cycles of treatment depending on the regimen used) is also a key determinant of the need for the addition of involved site or nodal radiation as part of combined modality therapy. This review summarizes the important role of interim and end of chemotherapy FDG-PET scanning to guide individualized initial therapy for patients to achieve optimal treatment outcomes.

Nivolumab-AVD Is Better Tolerated and Improves Progression-Free Survival Compared to Bv-AVD in Older Patients (Aged ≥60 Years) with Advanced Stage Hodgkin Lymphoma Enrolled on SWOG S1826

Background: Survival rates in patients (pts) with classic Hodgkin lymphoma (HL) aged ≥60 years (y) are lower than younger pts. The difference is due to comorbidities, impaired performance status, decreased chemotherapy tolerance, and increased treatment-related toxicity and mortality. The frontline regimen Bv-AVD can be challenging to administer in older patients due to toxicities, particularly infection and neuropathy. The PD-1 pathway is central to pathogenesis of HL; PD-1 blockade is effective in HL. The randomized, phase 3 trial, S1826, was conducted by the National Clinical Trials Network to evaluate N-AVD vs Bv-AVD in pts with newly diagnosed advanced stage (AS) HL and enrolled 994 pts; 97 were eligible and aged ≥60y. Methods: In this subset analysis, eligible pts were ≥60y with stage 3-4 HL. Pts were randomized 1:1 to 6 cycles of N-AVD or Bv-AVD. G-CSF neutropenia prophylaxis was optional with N-AVD and required with Bv-AVD. Pre-specified pts could receive radiation therapy (RT) to residual lesions on end of treatment PET. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. Response and progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), event-free survival (EFS), and detailed toxicity and safety events. EFS events were death without progression, progression/relapse, receipt of non-protocol systemic anti-lymphoma therapy without progression, or receipt of RT in a pt not declared eligible for RT at registration or who did not meet protocol-specified criteria for RT. Results: 97 pts aged ≥60y were enrolled from 7/9/19-10/5/22 and were randomized to N-AVD (n=48) or Bv-AVD (n=49). Median age was 66y (range, 60-83y), 62% were male, 86% were white, 3% were black, and 10% were Hispanic. 61% had stage IV disease and 47% had IPS 4-7. 69% of pts on N-AVD and 92% of pts on Bv-AVD received any G-CSF. No pts received RT per protocol. 95 pts were evaluable for safety analysis. While grade (gr) ≥3 hematologic toxicity occurred in 52% of pts on N-AVD and 38% on Bv-AVD (gr 3 neutropenia 48% vs 30%), febrile neutropenia, sepsis, and infections were lower for pts who received N-AVD vs Bv-AVD. (Table) Peripheral neuropathy was much less frequent with N-AVD than Bv-AVD in overall incidence (sensory: 31% vs 66% and motor: 8% vs 15%, respectively) and severity (grades ≥2, sensory: 10% vs 49% and motor: 0% vs 8%, respectively). (Table) The following adverse events, AEs (mainly &amp;lt;gr 3) were less frequent on N-AVD vs Bv-AVD: nausea (38% vs 62%), diarrhea (25% vs 45%), anorexia (15% vs 38%) and weight loss (4% vs 36%). Hypothyroidism (15% vs 0%), and rash (16% vs 2%, no gr ≥3) were more frequent on N-AVD than Bv-AVD; rates of other immune-related toxicities were similar between arms. In this subset analysis, median follow-up 12.1 months, PFS was superior in the N-AVD arm [HR 0.35 (95% CI 0.12-1.02) stratified one-sided logrank p=0.022]; 1-yr PFS was 93% (95% CI 79-98%) for N-AVD and 64% (95% CI 45-77%) for Bv-AVD. (Figure) 1-yr EFS was 93% (95% CI 79-98%) for N-AVD and 57% for Bv-AVD (95% CI 38-72%) [HR 0.19 (95% CI 0.06-0.61) stratified one-sided logrank p=0.0011]. 1-yr OS was 95% (95% CI 83-99%) for N-AVD and 83% (95% CI 67-92%) for Bv-AVD [HR 0.35 (95% CI 0.07-1.75) stratified one-sided logrank p=0.091]. On N-AVD, there were 2 deaths (due to infection/sepsis) and 3 progressions/relapses; on Bv-AVD, there were 7 deaths (5 due to infection/sepsis, 1 to pneumonitis, 1 unknown) and 8 progressions/relapses. Non-relapse mortality was 4% for N-AVD vs 14% for Bv-AVD. Treatment was discontinued early in 5 pts (10%) on N-AVD and 16 pts (33%) on Bv-AVD. N was discontinued early in 7 pts (15%) and Bv in 19 pts (39%). Reasons for discontinuation included (N vs Bv): AE (5 vs 14 pts), death (1 vs 3 pts), and disease progression (0 vs 1 pt). Conclusions: N-AVD improved PFS and EFS, and was better tolerated than Bv-AVD in pts aged ≥60 with AS HL. Substantially more pts discontinued Bv-AVD than N-AVD, primarily due to toxicity. Fewer deaths occurred on N-AVD than Bv-AVD. N-AVD is poised to become a standard of care for older AS HL pts fit for anthracycline-based combination therapy. Funding provided by the National Cancer Institute of the National Institutes of Health CA180888, CA180819, CA180821, CA180820, CA180863, CA189955 and funding/drug provided by BMS, drug provided by SeaGen for pts enrolled in Canada.

Age-Based Validation of the Advanced-Stage Hodgkin Lymphoma International Prognostic Index (A-HIPI) in a Real-World Danish Study: Suboptimal Performance in Older Patients

Purpose: Improved predictive tools are desired in classic Hodgkin lymphoma (cHL) to improve prognostication and to better risk stratify patients (pts) for clinical trials. In younger pts who tolerate intensive therapies, focus has been on limiting late treatment toxicity through risk-adapted, PET-guided treatment strategy. In older pts, acute treatment toxicities are limiting factors for optimal disease control. Due to these fundamental differences, predictive tools may perform differently in younger and older pts. In particular, tools developed in younger pts may be suboptimal in older populations and vice versa. The primary objective of this study was to assess the performance of the A-HIPI (development was limited to 18-65 years of age) against the international prognostic score (IPS) for modelling overall survival (OS) and progression-free survival (PFS) in younger and older pts with cHL. Methods: This study utilized data from the population-based, nationwide Danish National Lymphoma registry. Pts with advanced-stage cHL (Ann Arbor stage III-IV or IIB with extra nodal disease) were included and categorized by age in two groups: ages ≤65 years vs. &amp;gt;65 years. In the primary analysis, all pts regardless of therapy were included. A sensitivity analysis restricting to pts starting on BEACOPP or ABVD was performed (Only ABVD in the &amp;gt;65 cohort). Concordance index (C-index) and calibration were used to assess model performance and generalizability. Calibration was visualized using calibration plots and quantified by calibration in the large (CITL) and calibration slope (CS) at 5-years post diagnosis. Results: A total of 893 advanced-stage HL pts fulfilled the inclusion criteria (634 in the ≤65 cohort and 259 in the &amp;gt;65 cohort). The 5-year OS and PFS in the &amp;gt;65-year cohort were 44% (Confidence intervals (CI); 37-51%) and 35% (CI; 30-42%), respectively. Fifty-six pts in the &amp;gt;65 cohort were classified as low-intermediate-risk (IPS; 1-2), 128 intermediate-risk (IPS; 3-4), and 75 high-risk (IPS; 5-7). For the ≤65 cohort, the 5-year OS and PFS was 88% (CI; 85-90%) and 76% (CI; 73-80%), respectively. Twenty-three pts were classified as low-risk (IPS; 0), 244 low-intermediate-risk, 286 intermediate-risk, and 81 high-risk. The A-HIPI had a C-index of 0.74 and 0.63 for OS and PFS, respectively in the ≤65 years cohort vs. 0.65 and 0.64 for OS and PFS, respectively, in the &amp;gt;65 cohort. The IPS had a C-index in the ≤65 cohort of 0.66 and 0.60 for OS and PFS, respectively, vs. 0.58 and 0.59 for OS and PFS, respectively, in the &amp;gt;65 cohort (i.e., the IPS performed better in the ≤65 cohort in terms of OS and PFS but was inferior to the A-HIPI). When restricting to pts treated with ABVD or BEACOPP, the A-HIPI C-index in the &amp;gt;65 cohort (116 pts) were reduced to 0.55 for OS and 0.54 for PFS. For the ≤65 cohort (595 pts), the A-HIPI C-index was stable at 0.75 and 0.62 for OS and PFS, respectively. In terms of A-HIPI calibration in the &amp;gt;65 cohort, CITL and CS were -0.78 and 0.39 for OS vs. -0.98 and 0.80 for PFS. In the ≤65 cohort, CITL and CS were -0.06 and 0.99 for OS vs. 0.21 and 1.18 for PFS. Visual inspection of the calibration plot (Figure 1) for the &amp;gt;65 cohort showed that the A-HIPI underestimated the observed proportion for both OS and PFS (i.e., the observed events were higher than the predicted). Calibration plot for the ≤65 cohort (Figure 2) indicated that the A-HIPI accurately modelled the observed proportion for both OS and PFS (i.e., the predicted probability was consistent with the observed proportion). Conclusion: The newly developed A-HIPI was validated in a large population-based cohort of Danish pts with advanced-stage cHL. Performance of the A-HIPI was high in the ≤65 cohort and superior to the IPS for OS prediction. Calibration of A-HIPI was excellent in pts ages ≤65 years. However, A-HIPI performed significantly worse among pts &amp;gt;65 years and attained poor performance in pts receiving ABVD or BEACOPP, which is not surprising since patients older than 65 were not included in the development. This study emphasizes the importance of further efforts to develop or update models that apply specifically in older individuals. The inclusion of additional variables reflecting comorbidities and pts fitness into a prognostic model may be necessary to effectively deliver accurate prognoses and risk assessments for the older pt.

Pregnancies and Childbirth Following Advanced-Stage Hodgkin Lymphoma Treatment with Brecadd or Beacopp in the Randomized Phase III GHSG HD21 Trial

INTRODUCTION The GHSG-HD21 trial in adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) compares BrECADD (Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Superior treatment-related morbidity (TRMB) and at least non-inferior efficacy of BrECADD with high progression-free survival (PFS) rates after three years were presented previously. Fertility following chemotherapy is a major concern for these mostly young AS-HL patients. Therefore, we analyzed pregnancies and childbirth rates reported in HD21. METHODS This international open-label phase III trial included adult patients aged ≤ 60 yrs with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. Frequency of pregnancies among patients or their partners were analyzed in all female patients below 40 years and male patients below 50 years included in the ITT cohort for the safety endpoint TRMB. Descriptive statistics were used to report pregnancy rates. Childbirth rates per year were compared to German population data for women between 18-40 years in the years 2016-2020, obtained from the German Federal Statistical Office (Destatis). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. RESULTS Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries and 233 trial sites. The final cohort for this analysis comprised 1200 patients (496 women and 704 men; 80.1% of ITT). Baseline characteristics were well balanced between treatment arms and median follow-up for this analysis was 40 months. 55.6% of the patients had cryocpreservation prior to chemotherapy (46.1% women, 76.4% men). At time of this analysis, there were 126 reported pregnancies during follow-up. Data was incomplete in 25 cases, and these were excluded from analysis. Overall, 97 (9.1%) patients had at least one documented pregnancy; 38 (7.2%) and 53 (9.8%) in eBEACOPP and BrECADD arm, respectively. Nine patients had more than one pregnancy. Compared to eBEACOPP, pregnancy rates following BrECADD were higher in males (5.7% vs. 2.5%) and females (13.2% vs. 11.8%). 8.2% of patients with reported pregnancy made use of cryopreservation. 82.2% of all pregnancies resulted in childbirth and 17.9% ended early (4% due to induced abortion; 13.9% due to abortion). Among patients with reported childbirth, there was a greater proportion of female patients vs. partners of male patients (63.9% vs. 36.1%); otherwise there were no notable differences between baseline characteristics or total cycles of chemotherapy in patients with reported pregnancy compared to the rest of the cohort. Median time from last day of chemotherapy until date of birth was 32 months (range 4-57). In women between 18 and 40 years, the childbirth rate per year increased during the first two years after treatment (first year: 0.6% [CI95: -0.1-1.3]; second year: 4.4% [CI95: 2.4-6.3]) and were numerically above the population reference (6.51%) starting from the third year (third year: 8.8% [CI95: 5.9-11.7]; fourth year: 8.0% [CI95: 4.5-11.4]; fifth year: 7.8% [CI95: 2.9-12.8]). CONCLUSION We report high rates of pregnancy following chemotherapy in the HD21 trial; approximately one tenth of patients below age 40 (female) or 50 (male) in the HD21 trial have reported a pregnancy during follow-up. Compared to eBEACOPP, pregnancy rates were twofold higher in partners of men who received BrECADD and slightly higher in women. Notably, childbirth rates in women after the second year of follow-up were comparable to the German population. Together with unparalleled primary cure rates achieved with BrECADD, our data supports its use in young patients with a desire to have children.