Advanced Stage Classical Hodgkin Lymphoma Research Articles

Tolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma: GHSG HD21, a randomized study.

LBA7000 Background: We hypothesized that therapy with the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) guided by positron emission tomography after two cycles (PET2) could improve the treatment of advanced-stage classical Hodgkin lymphoma (AS-cHL). The HD21 trial aimed at demonstrating superiority over the intensified BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in terms of treatment-related morbidity (TRMB) and non-inferiority (NI) in terms of progression-free survival (PFS). This is the first report of the final confirmative analysis of the HD21 trial. Methods: HD21 is an international, open-label, randomized phase III trial including AS-cHL patients 18-60 years at diagnosis. Patients were randomized to receive individualized 4 or 6 cycles of either BEACOPP or BrECADD guided by PET2 results. The co-primary endpoints included TRMB and PFS, which had been successfully established recently. Testing for superiority was planned with mature follow-up of four years. An adjusted alpha level of 0.047 was required to cross the efficacy boundary for superiority. The trial was conducted in accordance with ICH-GCP (NCT02661503) and supported by a research grant from Takeda Oncology. Results: The ITT (intention-to-treat) cohort for the efficacy analysis consisted of 1482 patients, of which 742 were randomized to receive BrECADD and 740 to BEACOPP. Median age was 31.1 years (range 18 to 60), 44% were female. PET2 was negative in 424 (57.5%) and 426 (58.2%) patients for BrECADD or eBEACOPP, respectively, and these were scheduled for 4 treatment cycles. With median follow-up of 48 months, 4y-PFS was 94.3% for BrECADD (95%-CI 92.6-96.1), and 90.9% for BEACOPP (95%-CI 88.7-93.1). The hazard ratio was 0.66 [95% CI 0.45-0.97], p=0.035). PFS benefit of BrECADD was driven by a reduction in early treatment failures, i.e., primary progression within 3 months (5 vs. 15) or early relapse between months 3 and 12 (11 vs. 23) and observed across all investigated subgroups. PET2-negative patients in the BrECADD group showed a 4-year PFS of 96.5%. 4-year OS was 98.5% for BrECADD and 98.2% for BEACOPP. Analyses of gonadal function demonstrated significantly higher follicle stimulating hormone recovery rates after one year in both men (67% vs. 24%) and women (89% vs. 68%) with higher birth-rates in the BrECADD group (n=60 vs. n=43). Conclusions: BrECADD is significantly more effective than BEACOPP and is associated with an unprecedentedly high 4-year PFS, reducing the risk of progression, relapse or death by a third. Together with an abbreviated treatment duration of only 3 months for the majority of patients and a favorable tolerability, treatment with PET2-individualized BrECADD sets a new benchmark for the treatment of adult patients with AS-cHL. Clinical trial information: NCT02661503 .

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 < 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 & 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.

Identification of Risk Categories from the Advanced-Stage Hodgkin International Prognostic Index (A-HIPI) Model: A Detailed Analysis from the Hodgkin Lymphoma International Study for Individual Care (HoLISTIC) Consortium

Background: Prognostic modeling allows personalized risk prediction for individual patients (pt). The A-HIPI model in advanced stage classical Hodgkin lymphoma (AS-HL), developed and validated by the HoLISTIC Consortium (www.hodgkinconsortium.org), generates the individualized probability of a progression-free survival (PFS) event or death (OS) within the first 5 years (y) from diagnosis in pts based on continuous variables (www.qxmd.com/calculate/calculator_869/a-hipi). Clinical prognostic tools in lymphoma (eg, IPS, IPI, FLIPI, etc) typically use groupings of categorical values to define risk. Grouping a continuous value often results in loss of information, and most tools are not predictive for individual pts. However, discrete groupings have clinical utility & practicality for a) defining pt populations for clinical trials & real world studies, b) stratification within clinical trials, and c) crafting treatment guidelines. We studied potential approaches for utilizing the A-HIPI model to generate risk groups with input on strengths & limitations from the HoLISTIC modeling team & clinical experts. Methods: The A-HIPI model was developed via TRIPOD guidelines on 4,022 pts treated on 8 international clinical trials for AS-HL (Rodday. JCO 2023). External validation was performed on a dataset of 1,431 pts from 4 prospective registries. The 5y PFS (PFS5) in the A-HIPI development dataset was 77% (95% CI: 76-78); the 5y OS (OS5) was 92% (95% CI: 91-93). This represented the average outcome for a pt with AS-HL pt naïve to other clinical data at presentation. The distribution of PFS5 & OS5 predictions were heavily skewed (ie, asymmetric distribution) in both the A-HIPI discovery and validation dataset. While not unexpected due to the excellent PFS & OS in this disease setting, this presents challenges in the delineation of risk groups as depicted below . Three approaches were examined for the generation of A-HIPI risk groups. Proposed cutoffs were defined using the distribution of A-HIPI risk scores and data from the model-building cohort (ie, clinical trials). Validation was done using the A-HIPI validation cohort (ie, HL registries). Results: Approach 1: Risk groups based on clinical thresholds. Clinicians were queried what estimates of PFS5 would constitute high vs low risk. The positive, right-skewed distribution of A-HIPI risk scores limited this approach ( Figure), as cutoffs of PFS5 <70 and PFS5> 90 would only identify 15% and <1% of the population, respectively. Approach 2: Risk groups based on deviation from “average” pt. The 5-y PFS was 77% (95% CI: 76-78). We explored defining “standard risk” based on this confidence interval as well as clinical boundaries, with pts above or below this classified as decreased or increased risk, respectively. Results of a +/-5% clinical boundary are presented in the Table. Approach 3: Risk groups based on “ranking” of pts. Here we ranked the A-HIPI risk scores of the 4022 AS-HL pts in the model building cohort and used the distribution of the risk scores as a benchmark. The risk profile for a future pt is then compared to this distribution (eg, how do you rank compared to your peers). Continuous results are often presented this way (eg, tertiles or quartiles). It also allows flexibility for the user to define the size of the risk groups and/or clinical threshold of interest. Application of this approach showed good alignment between the predicted model percentiles and the observed distribution of scores in the validation cohort ( Table). This is also reflected in calibration curves presented in the primary manuscript. An online application (eg, R-Shiny) will be provided at the meeting to allow users to define their own cutoffs to aid in pt prognostication as well as identify populations for clinical trial development. Conclusions: There are challenges with defining risk groups from individual risk prediction modeling in AS-HL. Different applications and purposes, the skewed distribution of events/risk estimates, as well as varying clinical definitions of high risk, make it challenging to define consensus expert-based risk groupings for AS-HL. A flexible “rank-based” approach appeared to provide the most clinical utility & data granularity, which may be leveraged for clinical trial design and pt stratification. Further analysis and discussion of how to optimally define high-risk and low-risk populations in AS-HL will be needed as new therapeutic options emerge.

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 (>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.

Is Interim PET a Useful and Used Tool in Classical Hodgkin Lymphoma? Results from a Retrospective Multicenter Italian Experience

INTRODUCTION Interim PET (iPET) scan after 2 cycles has been proved a useful tool in order to escalate treatment in the setting of advanced stage (AS) classical Hodgkin Lymphoma (cHL) treated with ABVD as first-line therapy. However, few data are known regarding the use of iPET and the adoption of intensification treatment strategies in real life. MATERIALS AND METHODS We conducted a retrospective, multicenter study in which we collected consecutive, newly diagnosed AS cHL patients (pts) treated between January 2010 and December 2018. Pts could be included if aged 18 to 80 years old, if treated with ABVD/ABVD-like schemes and if pre-treatment and interim PET scans were available. Primary endpoint was the frequence of intensification after a positive iPET. Secondary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) of pts undergoing iPET-based intensification strategies. iPET was defined as positive or negative based on the assessment by the local investigator. When available, Deauville Score (DS) was also collected. Continuous covariates were summarized as median, interquartile distance (IQR) and range, categorical variables were summarized as absolute and percentage frequencies. Survival functions were defined as the time between the date of iPET to the date of progression (PFS) or death for any cause (PFS/OS) or last clinic control (PFS/OS) for censored cases. The survival functions were computed by means of Kaplan-Meier method. Comparisons between groups were done using the log-rank test; the effect of covariates was estimated using the Cox proportional hazard regression model and was expressed as hazard ratio (HR), with 95%CI. All the p-values reported were two-sided. RESULTS Detailed characteristics of the 399 enrolled pts are listed in Table 1. iPET was positive in 68 pts (17%), of whom 17 (25%) were immediately shifted to intensified therapies: 8 escBEACOPP (eB), 8 chemo+ASCT (cA), 1 other salvage regimens (oSR). DS was reported in 220 (55%) pts. In iPET-positive pts, DS was reported in 35/68 pts (51,4%): 25 were DS4 and 10 were DS5, respectively. Among the 51 iPET positive pts who didn't change treatment after iPET, 31 (61%) underwent a subsequent iPET after 4 cycles. iPET4 was positive in 17 pts (55%), of whom 12 (70%) were shifted to intensified treatments: 2 eB, 8 cA, 2 oSR. Overall, 29/68 iPET-positive pts (43%) were intensified either immediately after iPET or after a subsequent iPET4 positivity and the most commonly used intensification was cA (16/29 cases). After a median follow up of 6 years (0.2 - 12), 5-y PFS was 76% (95% CI 72 to 80%), and 5-y OS was 94% (95% CI 91 to 96%). In univariable analysis, iPET positivity (5y PFS 60% versus 80% for iPET negative pts, p < 0.001), stage IV, age (continuous form) and not receiving radiotherapy were significantly associated with worse PFS; iPET positivity (5y OS 82% versus 96% in iPET-negative pts, p=0.003), stage IV, age ≥ 60, IPS, B symptoms, male gender and not receiving radiotherapy were significantly associated with worse OS. PFS and OS were similar (p=0.851 and 0.520, respectively) for iPET-positive pts undergoing or not undergoing immediate intensification (59% versus 61%, and 84% versus 81%, respectively) [Figure 1]. The 5-y PFS and OS were significantly different between pts with iPET negativity and iPET positivity, as reported above. Remarkably, among iPET+ pts, no treatment modification after iPET positivity (either after 2 or 4 cycles) was associated with worse 5-Y PFS and OS (72% and 82% respectively) if compared to PET negative pts. Moreover, there were no differences in terms of both PFS and OS for iPET pts who modified treatment after either iPET or iPET4. CONCLUSIONS In AS cHL pts undergoing ABVD first line treatment, iPET positivity is 17%, but few pts shifted to intensification strategies and most pts didn't change treatment and underwent to iPET4. iPET4 was positive in 17/31 pts, of whom 70% shifted to salvage treatments, mainly cA. iPET prognostic role was confirmed, since PFS and OS were strongly correlated with iPET status, but early intensification didn't provide any PFS and/or OS advantages. Due to the high prognostic role of iPET positivity, AS cHL pts might benefit from more intensive first line treatments that could reduce iPET positive cases (e.g. AVD combos with anti-PD1 or brentuximab vedotin) or from more efficacious second line therapies (e.g. Brentuximab Vedotin and/or anti-PD1 based combination strategies)

Brentuximab vedotin with dacarbazine or nivolumab as frontline cHL therapy for older patients ineligible for chemotherapy

AbstractOlder patients with advanced-stage classical Hodgkin lymphoma (cHL) have inferior outcomes compared with younger patients, potentially due to comorbidities and frailty. This noncomparative phase 2 study enrolled patients aged ≥60 years with cHL unfit for conventional chemotherapy to receive frontline brentuximab vedotin (BV; 1.8 mg/kg) with dacarbazine (DTIC; 375 mg/m2) (part B) or nivolumab (part D; 3 mg/kg). In parts B and D, 50% and 38% of patients, respectively, had ≥3 general comorbidities or ≥1 significant comorbidity. Of the 22 patients treated with BV-DTIC, 95% achieved objective response, and 64% achieved complete response (CR). With a median follow-up of 63.6 months, median duration of response (mDOR) was 46.0 months. Median progression-free survival (mPFS) was 47.2 months; median overall survival (mOS) was not reached. Of 21 patients treated with BV-nivolumab, 86% achieved objective response, and 67% achieved CR. With 51.6 months of median follow-up, mDOR, mPFS, and mOS were not reached. Ten patients (45%) with BV-DTIC and 16 patients (76%) with BV-nivolumab experienced grade ≥3 treatment-emergent adverse events; sensory peripheral neuropathy (PN; 27%) and neutropenia (9%) were most common with BV-DTIC, and increased lipase (24%), motor PN (19%), and sensory PN (19%) were most common with BV-nivolumab. Despite high median age, inclusion of patients aged ≤88 years, and frailty, these results demonstrate safety and promising durable efficacy of BV-DTIC and BV-nivolumab combinations as frontline treatment, suggesting potential alternatives for older patients with cHL unfit for initial conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

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.

Comprehensive Analysis of Treatment Related Morbidity and Progression -Free Survival in the GHSG Phase III HD21 Trial

INTRODUCTION The GHSG-HD21 trial for newly diagnosed adult patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) compares the BrECADD regimen (Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in a PET adapted approach. Separate analyses of the co-primary endpoints for tolerability and efficacy demonstrated a significant and relevant reduction in treatment-related morbidity (TRMB) and non-inferiority of PFS, respectively. Here, we report the first combined comprehensive analysis of the primary endpoints of the HD21 trial. 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 21-day cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. At a planned interim analysis at 36 months follow-up, the efficacy endpoint PFS was determined in the ITT cohort comprising 1,482 patients (eBEACOPP n=740, and BrECADD n=742) while the safety endpoint TRMB was determined in 1,470 patients (BEACOPP n=732, and BrECADD n=738). Subgroup analyses were calculated with 95% confidence intervals (Cis). 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 across 233 trial sites. Actual median follow-up for this analysis was 40 months. Baseline characteristics were well balanced between treatment arms, median age was 34 yrs (range 18-61), and 47% were high-risk (international prognostic index IPS ≥ 3). Overall, the relative risk for a TRMB event was 0.72 (95% CI, 0.65-0.79) in favor of BrECADD. Subgroup analyses confirmed a consistent, highly significant TRMB benefit in all relevant subgroups. Dose reductions were required less frequently with BrECADD than with eBEACOPP (figure 1); full dose treatment at cycle 4 was administered in 58.5% of patients in the eBEACOPP group compared to 77.8% in the BrECADD group. In PET2-positive patients at cycle 6, full dose treatment was received by 42.5% in the eBEACOPP group versus 67.3% in the BrECADD group. Most frequent reasons for dose reductions were leukopenia for eBEACOPP (in 33.7% of patients) and thrombocytopenia for BrECADD (in 23.1 % of patients). 59% of patients achieved a PET2-negative response and were treated with a total of 4 cycles in each group; conversely, 41% of patients were PET2-positive and received 6 cycles. At the end of treatment with either 4 or 6 cycles, a complete metabolic response was seen in 80% and 82% of patients in the eBEACOPP and BrECADD cohorts, respectively. The 3-yr PFS was 94.9% for BrECADD (95% CI 93.5% - 96.7%), and 92.3% for eBEACOPP (95% CI 90.3% - 94.3%), with a corresponding HR of 0.63 (95% CI 0.42-0.94). A HR favoring BrECADD was consistently observed across all relevant subgroups (figure 2). Notably, HRs favoring BrECADD were generally lower in lower-risk cohorts including IPS (0, 1; 2, 3; 4-7: HR 0.45, 0.59, 0.87, respectively), stage (Ann-Arbor stage II, III, IV: HR 0.35, 0.6, 0.78, respectively), or PET-2 response (negative versus positive, HR 0.4, 95% CI 0.21-0.76 vs 0.78, 95% CI 0.44-1.38). Corresponding 3-yr PFS rates for BrECADD versus eBEACOPP were 97.1% (95% CI 95.5% - 98.7%) versus 93.6% (95% CI 91.3% - 95.9%) for PET2-negative patients and 93.5% (95% CI 90.6% - 96.5%) versus 90.6% (95% CI 87.1% - 94.1%) for PET2-positive patients, respectively. CONCLUSION With the novel BrECADD regimen, we observed the highest 3-yr PFS rates reported to date in a randomized clinical trial in advanced-stage cHL. Our analyses suggest that the unexpectedly high and improved efficacy of the new BrECADD regimen compared to eBEACOPP is a direct consequence of its improved tolerability and deliverability. Importantly, while the larger patient cohort of PET2-negative patients achieves a very high 3-yr PFS of 97% with a very short and safe 12-week treatment, this benefit was also observed for PET2-positive patients. In conclusion, the optimized risk-benefit ratio of the BrECADD regimen combined with the individualized PET2-guided treatment duration sets a new benchmark for the treatment of adult patients with newly diagnosed advanced stage cHL

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine for Advanced Stage Classical Hodgkin Lymphoma: Efficacy and Safety Results from the Single Arm Phase 2 Study

Introduction: Brentuximab vedotin (BV) is an antibody-drug conjugate approved for multiple cancer types, including previously untreated stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine (AVD) in adults. The combination of BV and nivolumab are both individually active and well tolerated in patients with cHL and have distinct and complementary mechanisms of action. BV and nivolumab have been previously studied in combination and with multiagent chemotherapy as BV+AD (omitting vinblastine) and N+AVD. It was hypothesized that the combination of BV and nivolumab with doxorubicin and dacarbazine (AN+AD) would result in high response rates and a well-tolerated safety profile with potentially less toxicity than vinblastine-containing regimens. SGN35-027 (NCT03646123; EudraCT Number 2020-004027-17; Part B) is an open-label, multiple-part, multicenter, phase 2 clinical trial. Preliminary results of this study showed promising efficacy (objective response rate [ORR] 93%; complete response [CR] rate 88% at end of therapy [EOT]) with no cases of febrile neutropenia or grade 5 adverse events (AEs) (Lee ASCO 2022). Of the patients with stage III or IV cHL who relapse, most will relapse within 18 to 24 months of treatment initiation. Methods: Part B enrolled patients with stage II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Patients received up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D]). The primary efficacy endpoint was CR rate at EOT. Key secondary endpoints included safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas. Results: Fifty-eight patients were enrolled; all but 1 patient received ≥1 dose of study drug (data cutoff 22 May 2023). Median age was 35 years (range, 19-78 years). Among efficacy evaluable patients (n = 56), ORR (CR+ PR) at EOT was 95% (95% CI: 85.1, 98.9); CR rate was 89% (95% CI: 78.1, 96.0) (Table 1). A total of 88.3% (95% CI: 75.7, 94.6) of responders had a DOR of at least 24 months, and 88.4% (95% CI: 76.0, 95.0) of responders had a DOCR of at least 24 months. Seven patients (12%) had a PFS event: 6 with disease progression and 1 who died (sepsis, outside safety reporting period). The estimated PFS rate at 24 months was 88.3% (95% CI: 75.7, 94.6) (Figure 1). Median follow-up was 24.2 months (95% CI: 23.4, 26.9). The most common treatment-related AEs of any grade were nausea (37 patients [65%]), fatigue (28 patients [49%]), and peripheral sensory neuropathy (25 patients [44%]). Of the patients with treatment-related peripheral sensory neuropathy, most (23 of 25 patients [92%]) were grade 1 or 2; the remaining 2 patients had grade 3 peripheral sensory neuropathy. Dose modifications due to peripheral sensory neuropathy occurred in 9 patients (16%). Grade ≥3 treatment-related AEs occurred in 19 patients (33%) (most common: alanine aminotransferase increased in 6 [11%] and neutropenia in 5 [9%]). No febrile neutropenia or Grade 5 AEs occurred. Treatment-related serious AEs (SAEs) occurred in 8 patients (14%). Seven patients (12%) had a treatment-emergent AE that led to discontinuation of BV. Treatment-emergent immune-mediated AEs (IMAEs) occurred in 19 patients (33%); treatment-emergent IMAEs that occurred in ≥5% of patients were hypothyroidism (5 patients [9%]) and pneumonitis and rash maculopapular (3 patients [5%] each). All cases of pneumonitis resolved. Conclusions: The use of 2 active, targeted agents with distinct and complementary mechanisms of action for the frontline treatment of advanced stage cHL resulted in promising efficacy, safety, and tolerability. These results demonstrate continued tolerability of AN+AD with no new safety signals observed. AN+AD may provide a future first-line treatment option for patients with advanced stage cHL; long-term follow-up is ongoing.

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

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

The Association of Plasma Cell Density of the Microenvironment with Classical Hodgkin Lymphoma Stage

Background
 Plasma cells are important prognostic factors in various malignancies including Classical Hodgkin lymphoma (CHL). In the CHL microenvironment, plasma cells are the main prognostic factors, but research of relationship between plasma cell density in the microenvironment and CHL stage is still very limited. This study aims to determine the relationship between plasma cell density in the microenvironment and the CHL stage.
 
 Methods
 A case series procedure was conducted. The samples were paraffin blocks of CHL patients at Anatomic Pathology Department of Faculty of Medicine Universitas Sriwijaya/Mohammad Hoesin General Hospital. Among 47 cases of CHL diagnosed from 1st Januari 2018 to 30th November 2022, only 30 cases were included. Immunohistochemistry was performed by using specific antibody of plasma cells (anti-CD138 antibody). The number of plasma cells in each sample was calculated based on the expression of CD138 in the cell membrane and cytoplasm with weak-strong intensity. Then the cut-off point value was determined based on the ROC curve to classify the high and low plasma cell densities. The density of plasma cells was correlated to clinicopathological characteristics including age, sex, tumor location, CHL subtypes and stage. Statistical analysis was performed using Spearman test of SPSS with significant consideration if p<0.05.
 
 Results
 A high proportion (>10,9) of tumour-associated plasma cells of the tumor microenvironment was found in CHL advanced stage. Spearman test resulted in a significant correlation between density of plasma cell with advanced stage classical Hodgkin lymphoma (p=0.000).
 
 Conclusions
 There is significant relationship between high density of plasma cells with CHL stage.

Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma

AbstractIn the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

Brentuximab vedotin with AVD for stage II–IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial

Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per μL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. National Institutes of Health and National Cancer Institute.

Toxicities at one year follow‐up in patients with advanced stage classical Hodgkin Lymphoma: results from the randomized phase III HD21 trial by the German Hodgkin Study Group

Introduction: The HD21 trial compares BrECADD with eBEACOPP for the first-line treatment of advanced stage classical Hodgkin Lymphoma (AS-cHL). We previously reported a superior acute tolerability profile for BrECADD. However, persisting treatment sequelae as peripheral neuropathy or gonadal dysfunction are a major concern for survivors of AS-cHL. Accordingly, resolution of organ toxicities is highly relevant from the patient´s perspective. Therefore, we report treatment-related toxicities at twelve months follow-up (FU12) after treatment in HD21. Methods: Adult patients ≤60 years of age with AS-cHL were included in this ongoing international open label randomized phase III trial and randomized in a 1:1 ratio to receive PET2-guided 4–6 cycles of either standard eBEACOPP or experimental BrECADD treatment. For detection of treatment sequelae at FU12, non-hematological adverse events and serum levels of FSH levels are reported. 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. Baseline characteristics were well balanced between treatment arms. Documented FU12 was available in 1395/1470 (94.9%) patients in the ITT cohort. 557 (80.8%) and 566 (80.2%) patients had no documented toxicity following eBEACOPP and BrECADD, respectively. At FU12, grade 2 or higher PNP was reported for 17 (2.7%) patients following eBEACOPP and for 12 (1.9%) patients following BrECADD; however, no or only grade 1 PNP was reported for most patients in both treatment groups with 97.3% for eBEACOPP and 98.1% for BrECADD. Rate of PNP was numerically higher in patients receiving 6 cycles of chemotherapy (3.0%) compared to 4 cycles (1.9%). FSH levels at FU12 were available for 597 patients and were higher for patients who received eBEACOPP (mean FSH 29.4 and 31.8 after 4 and 6 cycles, respectively) compared to BrECADD (mean FSH 18.3 and 20.5 after 4 and 6 cycles, respectively. Other than PNP, most frequent organ toxicities at FU12 were classified as respiratory, thoracic or mediastinal disorders (4.4%), and cardiac disorders (2.9%). All other organ toxicities were rare and equally distributed between trial arms. Conclusions: Complete resolution of acute adverse events is frequent following either regimen in the GHSG HD21 study. However, less patients report higher grade PNP or impaired gonadal function at FU12 after treatment with BrECADD than after eBEACOPP. Accordingly, persisting toxicities were reported in only few patients after BrECADD. Although these results are indicate good overall tolerability, they still need to be complemented by patient-reported outcomes for which analyses are ongoing. The non-inferiority of the experimental BrECADD regimen also remains to be demonstrated to draw definitive conclusions. The research was funded by: Takeda Keywords: Hodgkin lymphoma, Molecular Targeted Therapies, Ongoing Trials Conflicts of interests pertinent to the abstract. P. Borchmann Consultant or advisory role: Takeda Oncology, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Amgen, Miltenyi Biotech Honoraria: Takeda Oncology, Novartis, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Miltenyi Biotech, Incyte, Abbvie Research funding: Takeda Oncology, Roche, Novartis, Merck Sharp & Dohme, Amgen

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

Background: Prognostication of progression-free survival (PFS) and overall survival (OS) in adults with advanced stage classical Hodgkin lymphoma (A-HL) resulted in the International Prognostic Score (IPS7) (Hasenclever, 1998). The original IPS7 used dichotomous variables and was principally reflective of treatment from the 1980's. Analyses of more recently treated patients (pts) illustrated altered utility of the IPS7 in the modern era (Moccia, 2012), as well as a simplified score, the IPS3 (Diefenbach, 2015). We developed and validated a modern A-HL model, known as A-HIPI, to predict PFS & OS by 5 years (y) using comprehensive individual patient data, including continuous data values, from international clinical trials and large prospective HL registries that were standardized, normalized & harmonized as part of the HoLISTIC Consortium. Methods: Model development was performed on a cohort of 4,027 pts treated on 8 international A-HL clinical trials, from 1996-2012 (ECOG 2496, SWOG 0816, HD2000, HD9601, HD0607, HD0801, UK Stanford V, RATHL). External validation was performed in a separate cohort of 1,512 A-HL pts treated with curative intent from 4 HL registries (BC Cancer, Princess Margaret Cancer Centre, Iowa/Mayo SPORE, Australia). Untreated A-HL pts with stage IIB, III or IV disease & ages 18-65y were included. The primary outcomes of 5y PFS & 5y OS were estimated with separate Cox models. Baseline predictors were: sex, stage, B symptoms, histology, any bulk (by trial definition), and continuous forms of age, white blood cell count, lymphocyte count (LC), hemoglobin, albumin & erythrocyte sedimentation rate. Multiple imputation was used for missing data. To consider possible non-linear relationships for continuous variables (age & all lab values), we examined plots & splines. We used backwards elimination (P<0.05) to develop the model. Internal validation with 200 bootstrap samples was conducted to estimate optimism and correct for overfitting. The final prediction equations applied optimism corrections to beta coefficients & hazard ratios (HR). The model was evaluated in the external validation cohort & compared using C-statistics. Model scores were also grouped by quartiles for visualization in Kaplan Meier (KM) curves. Results: Median age in the development cohort was 33y; 55% were male; nodular sclerosis was the most common histology (74%); 35% had any bulk; 73% B symptoms; and stage was distributed as 28% IIB, 39% III & 33% IV. KM estimators were 0.77 (861 events by 5y) for 5y PFS and 0.92 for 5y OS (280 events by 5y). Median follow-up was 52 months (Q1=36, Q3=90). See the Table for predictors included in the prediction models & optimism-corrected HRs. Of note, continuous age & LC values were both modeled with piecewise linear splines, which yielded non-linear, U-shaped relationships with PFS & OS (Table). Optimism-corrected C-statistics in the development model were 0.60 for 5y PFS & 0.71 for 5y OS. Most baseline characteristics and outcomes of the external cohort were similar besides a difference in stage (38% IIb, 30% III, 32% IV) and longer median follow-up (74 months, Q1=27, Q3=133) in the validation cohort. C-statistics for the A-HIPI model were 0.58 for 5y PFS and 0.72 for 5y OS in external validation. In comparison, C-statistics were 0.58 & 0.57 for 5y PFS and 0.66 & 0.66 for 5y OS for the IPS7 and IPS3, respectively. KM visualization of the grouped A-HIPI model quartile scores for OS is shown (Figure). Conclusion: Via state-of-the-art predictive modeling, we developed & externally validated the A-HIPI among >5,500 newly diagnosed A-HL pts from recent seminal clinical trials & prospective HL registries. We found unique prognostic variables significant for PFS vs. OS. Furthermore, we identified novel non-linear, U-shaped relationships between age and LC with survival. Collectively, the model will estimate 5y PFS & OS for A-HL pts based on individualized baseline values. A web-based calculator will be presented at ASH to simplify application of the A-HIPI. Despite inclusion of continuous variables (and non-linear relationships), there was modest enhancement in model performance for PFS vs. the IPS. However, we demonstrated meaningful improvement in prediction of 5y OS. Future modeling will include incorporation of differing treatment regimens & response-adapted imaging via multistate modeling to improve prediction of survival and also delineation of treatment-related late effects. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma: Updated Efficacy and Safety Results from the Single-Arm Phase 2 Study (SGN35-027 Part B)

Introduction Brentuximab vedotin (BV) and nivolumab are well tolerated and active treatments for patients (pts) with classical Hodgkin lymphoma (cHL). These agents were previously studied in first salvage therapy (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as first-line therapy in older adults (ORR 95%) (Yasenchak 2020). In ECHELON-1 study, BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) improved overall survival (OS) by 4.5 percentage points over doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (6-year OS estimate of 93.9% vs 89.4%) in pts with previously untreated stage III or IV cHL (Ansell 2022). In pts with limited stage I or II cHL, BV plus doxorubicin and dacarbazine (AD) treatment resulted in a CR rate of 97% at end of treatment (EOT), promising 4-year progression-free survival (PFS) estimate of 88%, and no cases of ≥ Grade 3 peripheral neuropathy (Abramson 2021). In Part B of SGN35-027, treatment with BV, nivolumab, doxorubicin, and dacarbazine (AN+AD) showed promising preliminary activity in pts with bulky stage II or stage III/IV cHL (at EOT: ORR 93%; CR 88%) with no cases of febrile neutropenia or Grade 5 adverse events (AEs) (Lee 2021). Herein, we present updated efficacy and safety results from Part B of this study. Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. In Part B, enrolled pts had Ann Arbor stage I or II cHL with bulky mediastinal disease (defined as ≥10 cm) or stage III or IV cHL. Pts were treated with up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m2 [A], and dacarbazine 375 mg/m2 [D]). All study drugs were administered intravenously on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Key secondary endpoints included safety, tolerability, ORR, duration of objective response (DOR), duration of complete response (DOCR), and PFS. Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) incorporating Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2016). Results In Part B, 58 pts were enrolled of which, 57 received at least 1 dose of study treatment. Most treated pts were White (88%) and <65 years old (95%), and approximately half were male (53%). The median age was 35.0 years (range: 19, 78 years). Thirty percent of treated pts had stage II cHL with bulky mediastinal disease, while the remainder had stage III (18%) or IV (51%) cHL. Of the 57 pts treated, the overall CR rate was 88% (95% CI: 76.3, 94.9) at EOT. ORR (CR or partial response [PR]) was 93% (95% CI: 83.0, 98.1) at EOT. With a median follow-up of 15.1 months, 4 pts (7%) had progressive disease and 1 pt (2%) died. The estimated PFS rate was 93% (95% CI: 81.6, 97.2) at 12 months. As of the data cutoff date (02-May-2022), 93% of pts (95% CI: 81.7, 97.2) had a DOR of least 12 months and 92% of pts (95% CI: 80.0, 96.9) had a DOCR of at least 12 months. Of the 58 pts enrolled, 4 pts had discontinued treatment (study treatment) early due to treatment-emergent adverse events (TEAEs) and 74% of pts had any dose modifications including any dose delay (28%), reduction (25%), and elimination (39%) due to AEs. Within 30 days of last dose of BV or 100 days of last dose of nivolumab, 51% of pts experienced ≥ Grade 3 TEAEs. Nausea, fatigue, and peripheral sensory neuropathy were the most frequently reported treatment-related TEAEs (65%, 47%, and 42% of pts, respectively). Notably, only 2 pts (4%) experienced ≥ Grade 3 peripheral sensory neuropathy, of which were considered treatment-related. No TEAEs led to death, and no cases of febrile neutropenia were reported. Eight pts (14%) experienced treatment-related serious TEAEs; most commonly pneumonitis (5%) and pyrexia (5%). Twenty pts (35%) experienced treatment-emergent immune-mediated AEs; most commonly hypothyroidism (9%), pneumonitis (5%), and maculo-papular rash (5%). Conclusions Efficacy results continue to show that AN+AD is a promising treatment for adult pts with bulky stage II or stage III/IV cHL. Updated safety results demonstrate continued tolerability with AN+AD and no new safety signals observed. Omitting bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. This study is ongoing and updated results will be presented.

Long-Term Outcomes of High-Risk Stage 1/2 Classic Hodgkin Lymphoma Managed with an Advanced Stage Treatment Approach

Background: The definition of advanced stage classic Hodgkin lymphoma (cHL) may vary, with bulky stage 2A (> 10cm or > 33% of transthoracic diameter otherwise described as 'large mediastinal adenopathy’ (LMA)) and/or stage 2B with risk factors, included in some studies and clinical guidelines. The ECHELON 1 study recently demonstrated improved overall survival (OS) using AVD-brentuximab vedotin (BV) compared with ABVD in stage 3/4 cHL (Ansell et al. NEJM 2022). Similarly, the pediatric combination BV-AVE-PC demonstrated improved event free survival (EFS) over ABVE-PC in a phase 3 trial of 'high risk patients (pts)’ age 2-21 years (y) (AHOD1331), a definition that included stage 2B bulky (LMA) pts, with a significant benefit shown in this subgroup (HR 0.09 (0.01-0.69)) (Castellino et al. ASCO 2022). Thus, re-evaluation of 'advanced stage’ definitions is warranted, especially in the adult population. Herein, we evaluated the long-term outcomes of pts with stages 1/2 bulky and 2B, a group that has been uniformly included in our advanced stage management approach. Methods: The BC Cancer Lymphoid Cancer Database was screened to identify all pts 16-70 y with 1/2A bulky (≥ 10 cm) and 2B (± bulky) disease treated with ABVD chemotherapy. Since 2005, advanced stage cHL pts in BC have been managed with 6 cycles of ABVD and PET-guided consolidative RT, whereby those with an EOT PET positive (pos) scan received RT. Following report of the RATHL trial in 2015, those pts with an interim PET2 negative (neg) scan had bleomycin omitted from the latter 4 cycles. For the current study, PET scans assessed by the IHP criteria were re-reviewed to assign a Deauville (D) score (PET-neg=D1-3, DX; PET-pos=D4-5). Freedom from treatment failure (FFTF) was measured from diagnosis to relapse/ progression of HL, or death due to HL or treatment toxicity. Results: From 2005-2020, 295 pts (148 M, 147 F) were identified. By stage: 1A bulky n=2, 2A bulky n=71 (henceforth called 'bulky only’ n=73); 2B n=133; 1B bulky n=3, 2B bulky n=86 (henceforth called stage 1/2B bulky n=89). Median age was 30 y (range 17- 69 y), median mass size 10 cm overall and 11 cm in bulky cases (range 10-20 cm). Of those with bulky disease (n=162), 147 (91%) had a bulky mediastinal mass. Using the reverse Kaplan-Meier method, median follow-up was 9.3 y (0.9 -17.3 y). The 5 y FFTF and OS for all pts were 84% and 94%. By stage groups, 5 y FFTF estimates were: 90% for bulky only, 82% in 2B, and 81% in 1/2B bulky pts (p=0.29) (Figure 1a), while corresponding 5 y OS estimates were 95%, 93%, and 94%, respectively (p=0.52) (Figure 1b). An EOT PET was performed in 250 pts and an additional 11 patients were included who only had a PET2-neg scan which was not repeated (total PET scan n= 261). The main reason for not having a PET scan was absence of residual mass on CT scan (21/34); 2 patients had progressive disease (PD) while on treatment (both stage 2B). In total 208/261(80%) had a PET-neg scan (2 pts received RT), and 53/261 (20%) had an EOT PET-pos scan of which, 32 (63%) received RT (mediastinal RT, 30/32). Stage 1/2B bulky cases were more likely to have a PET-pos scan (1/2B 32% vs 2B 18% vs bulky only 10%, p=0.002), and as a result, were more likely to receive RT (1/2B bulky 23% vs 2B 9% vs bulky only 6%, p=0.003). Overall, the 5 y FFTF was superior in PET-neg cases (93% vs 49%, p<0.001 (and 62.5% in PET-pos pts who received RT)), and 5 y OS was 96% vs 88% (p=0.17). For the 259 cases in which the D score was available, 5 y FFTF was similar across PET-neg D categories: DX 95%; D1 92%; D2 94%; D3 93%. For all DX-3, 5y FFTF was 94%, and superior to both D4 70% and D5 17% (p<0.001). Corresponding 5 y OS estimates for DX-D3, D4, and D5, were 96%, 95%, and 77%, respectively, with only the latter demonstrating an inferior prognosis (p=0.005). An EOT D5 PET scan was more common in pts with B symptoms: stage 1/2B bulky cases 12/83, 14.5%; 2B 10/106, 9%; bulky only 2/70, 3% (p=0.048). Conclusion: Applying an advanced stage management approach yields excellent outcomes, particularly in the 80% of patients with a PET-neg scan. Further, use of a PET-scan limited RT use to only 6% of pts with stage 1/2A bulky disease. However, those with stage 1/2B bulky disease have a higher likelihood of an EOT PET-pos scan and subsequent RT. Further, an EOT PET D5 score was more common in those with B symptoms overall, especially when coupled with bulky disease. This data provides further rationale for consideration of BV with upfront therapy in other advanced stage subgroups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Copy Number Alterations of Chromosome 9p24.1 in Elderly Patients with Advanced-Stage Classic Hodgkin Lymphoma Who Received ABVD: An Ancillary Analysis of Multi-Center Retrospective Study in Japan (HORIZON study)

Introduction Copy number alterations (CNAs) of chromosome 9p24.1 are frequently observed in patients (pts) with classic Hodgkin lymphoma (cHL), which result in increased expression of programmed death ligand-1 on Reed-Sternberg (RS) cells. The amplification of 9p24.1 was found in approximately 50% of pts with advanced-stage cHL, and was an independent prognostic factor for worse progression-free survival (PFS) (Roemer MG, et al. JCO. 2016). In addition, 9p24.1 CNAs is thought to be one of the potential predictive markers for response of immune checkpoint blockade for cHL (Gerhard-Hartmann E, et al. BJH. 2022). However, the incidence or prognostic impact of 9p24.1 CNAs in elderly pts with newly diagnosed advanced-stage cHL remains unclear. In this ancillary analysis of a multi-center retrospective study (HORIZON study, UMIN000033264), we evaluated clinical impact of 9p24.1 CNAs in elderly pts with newly diagnosed advanced-stage cHL who received a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Methods The key eligibility criteria of the current analysis were as follows: 1) pts with histologically diagnosed cHL between 2007 and 2016 in each institution; 2) advanced-stage cHL (stage III, IV or IIB with bulky or extranodal lesion); 3) age at diagnosis > 60 years; 4) had received at least one cycle of ABVD as initial treatment including a modified ABVD regimen (dacarbazine dose reduced to 250 mg/m2); and 5) had available specimen for tissue fluorescence in situ hybridization (FISH) analysis. All specimens were centrally reviewed by 3 experienced hematopathologists and confirmed the diagnosis of cHL. In the tissue FISH analysis, CNAs of the 9q24.1 loci along with the expression of CD30 were simultaneously detected using a combination of immunofluorescence with Fluorescence Immunophenotyping and interphase Cytogenetics as a Tool for Investigation of Neoplasia (FICTION), as described previously (Martínez-Ramírez A, et al. Leukemia. 2004). A median number of 50 RS cells (range: 30 to 74 RS cells) per case were analyzed. According to the previous report (Roemer MG, et al. JCO. 2016), nuclei with a target:control probe ratio of ≥ 3:1 were defined as amplification, and those with a probe ratio of > 1:1 but , < 3:1 were classified as relative copy gain. Nuclei with a probe ratio of 1:1 but more than two copies of each probe were defined as polysomic for chromosome 9p. In each case, the percent and magnitude of 9p24.1 amplification, copy gain, polysomy, and normal copy numbers (disomy) were noted. Cases were classified by the highest observed level of 9p24.1 CNAs. As survival analysis, overall survival (OS), PFS, and event-free survival (EFS; defined as the time from a diagnosis of cHL to disease progression or relapse, subsequent systemic chemotherapy for cHL, or death due to any cause), were evaluated. Results Among 99 eligible pts, the median age was 71 years (interquartile range [IQR] 65-77). The numbers of pts with an ECOG performance status (PS) 2 or more and B symptoms were 17 (17%) and 50 (51%), respectively. Sixty pts (61%) had mixed cellularity cHL, and 28 pts (28%) had nodular sclerosis cHL. Forty-five pts (45%) were positive for EBV-encoded small RNA (EBER) in situ hybridization. Hypoalbuminemia [serum albumin <4 g/dL] and anemia [hemoglobin <10.5 g/dL], were observed in 84 (85%), and 37 pts (37%), respectively. All the 99 pts had 9p24.1 CNAs; 67 pts (68%) had amplification, and the remaining 32 pts (32%) had copy gain (Figure 1). Hypoalbuminemia and anemia were significantly more frequent among pts with 9p24.1 amplification. The incidence of 9p24.1 amplification in EBER-positive cases tend to be higher than that of EBER-negative cases (78% in pts with EBER- positive vs. 59% in pts with EBER-negative, P=0.056). With a median follow-up duration of 52 months, the estimated OS, PFS, and EFS at 5 years in pts with 9p24.1 amplification were 80.1%, 64.2%, 59.9%, respectively. The estimated 5-year OS, PFS, and EFS of pts with 9p24.1 copy gain were 71.2%, 58.4%, 55.7%, respectively. No statistical differences were observed regarding these survival parameters between those pts with amplification and copy gain. Conclusion This ancillary analysis showed that hypoalbuminemia and anemia were significantly more frequent among pts with 9p24.1 amplification. Nevertheless, 9p24.1 amplification was not a prognostic factor for OS, PFS, and EFS in elderly pts with advanced-stage cHL treated with ABVD in the present study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pembrolizumab and Chemotherapy in Newly-Diagnosed, Early Unfavorable or Advanced Stage Classic Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Introduction: In a recent study, pembrolizumab followed by doxorubicin, vinblastine, and dacarbazine (AVD) had promising efficacy in patients (pts) with newly-diagnosed, early unfavorable, or advanced-stage classic Hodgkin lymphoma (cHL) (Allen et al. 2021; Blood 137:1318-26). The current phase 2 KEYNOTE-C11 study (NCT05008224) evaluates the safety and efficacy of pembrolizumab followed by AVD chemotherapy and pembrolizumab consolidation in pts with untreated, early unfavorable or advanced-stage cHL without radiotherapy. Here, we present results of a protocol-specified interim efficacy analysis. Methods: Eligible pts aged ≥18 years with newly-diagnosed, early unfavorable or advanced stage cHL received induction with pembrolizumab 200 mg IV on d1 every 3 weeks (Q3W) for 3 cycles. Pembrolizumab monotherapy was followed by PET2 to assess response. All pts then received 2 cycles of standard dose AVD on d1 and 15 for 2 cycles (chemotherapy phase 1), followed by PET3. PET3-negative pts (Deauville score 1-3) received 2-4 additional cycles AVD based on stage/bulk. Pts aged ≤60 yrs who were PET3-positive (Deauville score 4-5) received 2-4 cycles of escalated bleomycin plus etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (esc BEACOPP, chemotherapy phase 2). At the end of chemotherapy, all pts received consolidation with 4 cycles pembrolizumab 400 mg Q6W. A post-hoc interim analysis was performed for pts who had either reached or had discontinued treatment prior to PET3 response assessment. The primary analysis endpoints for this interim analysis were PET3 response (negativity rate) by investigator. The data cutoff date for the interim analysis reported here is July 15, 2022. Results: A total of 146 pts with untreated cHL were enrolled. The median (range) age was 34.5 yrs (18-78); 29 (20%) pts had bulky disease, 81 (55%) and 61 (42%), respectively, had advanced and early unfavorable disease, and 4 (3%) had missing data regarding disease group. At data cut-off, the median (range) follow-up was 3.2 mo (1.0-8.9). Of 146 pts, 46 (32%) were on pembrolizumab monotherapy, 42 (29%) were on chemotherapy phase 1, 34 (23%) were on chemotherapy phase 2, and 7 pts were on pembrolizumab consolidation. A total of 101 pts reached PET2 assessment or discontinued pembrolizumab monotherapy for any reason before PET2. Of these 26 (26%) were PET2-negative by investigator, 53 (52%) were PET2-positive, 9 (9%) discontinued treatment, and 13 (13%) had missing data. A total of 56 pts reached PET3 assessment or discontinued during chemotherapy phase 1. Of these, 38 (68%) were PET3-negative, 4 (7%) were PET3-positive, 11 (20%) had discontinued treatment, and 3 (5%) pts had missing data. Adverse events (AEs) of any grade occurred in 108 of 146 (74%) pts who received pembrolizumab monotherapy or consolidation, 63 of 89 (71%) who received AVD, and 1 of 2 (50%) who received BEACOPP. Grade ≥3 drug related adverse events were reported in 20 of 146 (14%) pts who received pembrolizumab monotherapy or consolidation, 48 of 89 (54%) pts who received AVD, and in 1 of 2 pts who received escBEACOPP. There were no deaths due to drug-related events. Immune mediated events were reported in 28 (19%) pts who received pembrolizumab monotherapy or consolidation. Most were low-grade 1-2 events reported in 20 (14%) pts, most commonly hyperthyroidism (5%) and hypothyroidism (3%). There were no deaths due to immune-mediated events. Conclusion: Pembrolizumab induction followed by chemotherapy was well tolerated in pts with newly-diagnosed, early unfavorable, or advanced-stage cHL, with 26% of pts achieving a PET2-negative response following the initial course of pembrolizumab alone and 68% having a PET3-negative response as assessed by investigator following the initial chemotherapy phase. Data from this PET-adapted regimen show promising antitumor activity and no safety concerns mid-treatment, indicating that this regimen may be an effective treatment option in this patient population. Data from the full preplanned protocol-specified interim futility analysis will be presented at the meeting.

Treatment Related Morbidity in Patients with Classical Hodgkin Lymphoma: Results of the Ongoing, Randomized Phase III HD21 Trial By the German Hodgkin Study Group

INTRODUCTION Interim PET (PET2)-guided intensive upfront treatment of newly diagnosed advanced stage (AS) classical Hodgkin Lymphoma (cHL) patients with eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). CD30-targeted therapy with the antibody-drug conjugate brentuximab vedotin (BV) has proven high efficacy and favorable tolerability in cHL. For the German Hodgkin Study Group (GHSG) HD21 study we thus hypothesized that using BV to remodel the eBEACOPP regimen could further decrease TRMB while maintaining the high efficacy of PET2-guided eBEACOPP. Here, we report the final analysis of the TRMB endpoint from the HD21 study. Methods This international open label randomized phase III trial included adult patients ≤ 60 years of age with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 cycles of either standard eBEACOPP or experimental BrECADD (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) treatment. PET2 was assessed by blinded panel review (PP-2). Reduction of TRMB was the first part of the co-primary endpoint, whereas non-inferiority of efficacy as determined by progression-free survival was the second part. TRMB was determined using the Cochran-Mantel-Haenszel method. Stratification factors included sex, age, International Prognostic Score (IPS), and location of trial site. TRMB was defined as any CTCAE grade 3 or 4 organ toxicity or grade 4 hematological toxicity (defined as anemia, thrombocytopenia, infection) during study treatment. Categorical variables were compared using fisher´s exact test. Exploratory analyses were performed for further safety outcome parameters. 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 more than 250 trial centers. The intention-to-treat (ITT) population comprised 1,470 patients. Baseline characteristics such as sex (56 % male), age (79% ≤45 years), IPS (54% 0-2), location (92% Europe), performance status (70% ECOG 0), B symptoms (68%), and Ann-Arbor stage III/IV (84%) were well balanced between the treatment arms. As recommended by PP-2, 59% of patients (n=861, eBEACOPP n=430, BrECADD n=431) received 4 cycles and 41% (n=609, eBEACOPP n=302, BrECADD n=307) received 6 cycles of therapy. TRMB was analyzed in the ITT cohort comprising 732 patients in the eBEACOPP and 738 patients in the BrECADD group. Overall, TRMB was documented in 59% and 42 % of patients in the eBEACOPP and BrECADD groups, respectively (relative risk for eBEACOPP 1.41; 95% CI, 1.27 - 1.56, p<0.001, relative risk for BrECADD 0.72; 95% Confidence interval [CI], 0.65 - 0.79, p<0.001). The relative risk estimates remained stable among the stratification factors (sex, age, IPS, location). In the eBEACOPP group 52% of patients had hematological TRMB events compared to 31% in the BrECADD group (p<0.001). The significant difference for hematological TRMB was reflected in the reduction in red cell and platelet transfusions. At least one red cell transfusion was given in 22% of patients in the eBEACOPP group and in 8% in the BrECADD group, and at least one platelet transfusion in 13% and 6%, respectively. Leukopenia grade 4 was observed in 94% and 87%, respectively. TRMB organ toxicity was documented in 17% of patients in the eBEACOPP group and 19% in the BrECADD group (p = 0.455). Peripheral sensory neuropathy all grades was documented in 49% and 38% in the eBEACOPP and BrECADD group, respectively, which was mainly grade 1 (33% and 31%), whereas grade 2 occurred in 14% and 6%, and grade 3 in 2% and 1%, respectively. Peripheral motor neuropathy all grades was documented in 4% in both treatment groups, which was grade 1 in 3%, and grade 2 in 1% in each group, respectively. CONCLUSION This analysis of the GHSG HD21 for patients with newly diagnosed AS-cHL shows a significant and clinically relevant reduction in treatment-related morbidities with BrECADD as compared to eBEACOPP.