Brentuximab Vedotin With Adriamycin, Vinblastine, and Dacarbazine for Patients Aged 18–59 Years With Untreated Advanced Stage Classical Hodgkin Lymphoma: The Largest Real‐Life Series From Southern Italy Cancer Centers

ABSTRACT

BV + AVD is increasingly used for frontline treatment of stage III/IV cHL. Young adults and adults (Ya&A) were the most common patients treated with BV + AVD in clinical trials but have not been studied in non‐trial settings. We conducted a real‐life study in secondary and tertiary cancer centers to evaluate the PFS in 18–59 years aged patients who were scheduled to receive six BV + AVD for newly diagnosed advanced stage cHL. This is the largest cohort of Ya&A reported to date including 150 patients from four clinical institutions in Southern Italy, all of which employed structured supportive care programs for HL. Fifty patients (30%) had at least one ECHELON‐1 ineligibility criterion, including comorbidities and/or adverse performance status. All 150 patients underwent BV + AVD with a median relative dose intensity of 100% (dose reduction and/or discontinuation ≥ 15%, in 11% of them). At end‐of‐treatment (EoT) FDG‐PET, 93% (140/147) of patients (three did not undergo EoT FDG‐PET due to early grade 5 toxicity) achieved a complete response (95% CI, 88.1–96.8). Altogether, four patients (2.7%) received consolidation radiotherapy of residual nodal masses with a Deauville score of 4. Grade ≥ 2 peripheral neuropathy, cardiotoxicity, and febrile neutropenia were reported by 13%, 7%, and 3% of patients, respectively. With a 24 month median follow‐up, PFS in the entire analyzed population was 91% (95% CI, 0.864–0.958). In Ya&A with high‐risk cHL, our data suggest that a BV‐driven strategy (without bleomycin and consolidation radiotherapy) is an effective up‐front option in oncologic centers specialized in HL care, improving the rate of durable complete remission in routine clinical practice.

Trial Registration: ClinicalTrials.gov identifier: NCT06857500

1. Introduction

Classical Hodgkin lymphoma (cHL) is commonly diagnosed in patients of 18–59 years of age, that is, Young adults and Adults (Ya&A), as shown in the National Cancer Institute register (August Report; https://www.cancer.gov) [1]. Clinically, these patients often present with negative prognostic factors such as advanced stage. Multiple international cooperative oncology groups have investigated new frontline treatments for Ann Arbor stage III/IV cHL, mostly in patients aged 18–59 years, within phase III trials [2, 3, 4, 5]. These treatments involve approaches based on increased dose density/dose intensity of traditional cytotoxic drugs (such as The Fondazione Italiana Linfomi [FIL]‐Rouge trial) [2] or new targeted agents such as nivolumab (the SWOG S1826 trial) [4, 5] or Brentuximab vedotin (BV) (the HD21 and ECHELON‐1 trials) [4, 5]. Among these, the optimal frontline regimen remains debated, not only due to acute toxicities and drug‐related costs, but also because of uncertainties in long‐term disease control [6, 7].

BV is a monoclonal antibody drug conjugated with a protease‐cleavable linker to the microtubule‐disrupting agent monomethyl auristatin E, which targets CD30 on the Reed‐Sternberg cells. The global, phase III ECHELON‐1 trial compared BV in combination with adriamycin, vinblastine, and dacarbazine (BV + AVD) versus adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed stage III/IV cHL [5, 8, 9, 10]. Among 1334 included patients, most cases were Ya&A (N = 1148; 86%). At the 51° National Congress of the Italian Society of Hematology, a post hoc analysis of the follow‐up data of the 18–59 years aged subgroup in the ECHELON‐1 trial was specifically conducted to evaluate the progression‐free survival (PFS) [11]. Ya&A received either BV + AVD (N = 580) or ABVD (N = 568): at 2‐year follow‐up, the Kaplan–Meier curve of PFS for BV + AVD flattened out with a plateau that constantly remained at 86% until 7 years with a number of 67 events versus the Kaplan–Meier curve of PFS for ABVD which declined during follow‐up to 79% with a number of 91 events (HR: 0.667; 95% confidence interval [CI]: 0.486–0.914; p = 0.011 by log‐rank test). According to the study design, no patient in either arm received consolidation radiotherapy for residual nodal masses (RNMs). Low rates of second malignancies (5% for BV + AVD vs. 6% for ABVD), no significant fertility impairment (pregnancies: 92 for BV + AVD vs. 73 for ABVD) and resolution or improvement of peripheral neuropathy in most patients, were reported [11]. Furthermore, the Ya&A subgroup showed a 7‐year overall survival of 97% (number of events, 21) for BV + AVD versus 92% (number of events, 39) for ABVD (HR: 0.489; 95% CI: 0.287–0.833; p = 0.007 by log‐rank test) with a 51% reduction in the risk of death for any cause [11]. These data underscore the clinical benefit of BV + AVD for patients aged 18–59 years, mostly regarding long‐term disease remission, with no new safety concerns. Based on trial clinical context data, BV + AVD is considered one of the standards of care for Ya&A with untreated advanced stage cHL [12, 13].

To date, no studies outside of prospective clinical trials have evaluated the efficacy and safety of BV + AVD in YA&A with newly diagnosed advanced stage cHL. Herein, we investigated the largest real‐world cohort reported to date of patients aged 18–59 years with stage III–IV cHL after frontline BV + AVD treatment, aiming to better understand treatment outcomes and specific toxicities in this age group in clinical practice. Patients were selected across four cancer centers in Southern Italy specialized in HL care, with robust supportive treatment protocols and certified programs for 2‐deoxy‐2[F‐18] fluoro‐d‐glucose positron emission tomography (FDG‐PET) site qualification as already reported [14, 15, 16, 17].

2. Patients and Methods

2.1. Patient Selection

Among patients with previously untreated and biopsy‐proven cHL, with Ann Arbor stages III–IV consecutively referred to oncology Units for curative‐intent antineoplastic treatment by using frontline BV + AVD, as described in the ECHELON‐1 study [5], we selected those aged 18–59 years from 1 November 2021 to 31 December 2024. All HL diagnoses were made according to the World Health Organization Classification for Lymphoid Neoplasms by expert hematopathologists applying the pathological criteria current at the time of diagnosis [18, 19, 20, 21]. This was a retrospective, multi‐center study based on the medical records and/or local databases of the Hematology Unit of the Federico II University of Naples (Italy), Oncology Unit of the Federico II University of Naples (Italy), Hematology Unit of the Antonio Cardarelli Hospital of national importance of Naples (Italy) and Hematology Unit of the Andrea Tortora Hospital of Pagani (Italy). These four clinical centers—one secondary and three tertiary—had similar internal guidelines for HL management (Supporting Information methods: Routine Clinical Evaluations) and were accredited for lymphoma treatment, as documented by AGENAS (https://trovastrutture.agenas.it/mappa/?term=Tumori%20rari%20linfomi&pid = 59) and FIL (https://filinf.it/elenco‐centri) reports. Particular attention was paid to supportive care (Supporting Information methods: Supportive Care). Primary anti‐infectious prophylaxis included lipegfilgrastim and various antimicrobial drugs, as already reported [14, 22, 23, 24] erythropoiesis‐stimulating agents (ESAs) were offered to patients with chemotherapy‐associated anemia whose hemoglobin declined to 10 g/dL; early peripheral neuropathy was managed using l‐acetylcarnitine and/or pregabalin, along with specific drug dose reductions (first vinblastine, then BV); cardiological toxicity was addressed with early use of angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, beta‐blockers and/or anti‐arythmic drugs according to echocardiographic monitoring (Figure 1) [25, 26, 27]. Noteworthy, the two nuclear medicine units (Federico II University Medical School of Naples, and IRCCS SYNLAB of Naples, Italy) involved in daily patient management, had obtained the ⁶⁸Ge phantom‐based FDG‐PET site qualification program as described in the GITIL/FIL HD0607 Trial [15, 16, 17].

FIGURE 1.

Drug doses, schedule, and treatment administration details of frontline BV + AVD regimen in the real life of young adults and adults. Dose‐intensity and dose‐dense of BV + AVD in cycles 1–6, and diagnostic work‐up and vigorous support treatments are also shown. BV + AVD = Brentuximab Vedotin, Adriamycin, Vinblastine, Dacarbazine; EoT = end‐of‐treatment; FDG‐PET/CT = 2‐deoxy‐2[F‐18] fluoro‐D‐glucose positron emission tomography/computed tomography.

All necessary approvals were obtained from the ethics committee (approval protocol number: 61/2025) and ClinicalTrials.gov (number, NCT06857500). The study was undertaken in accordance with the Declaration of Helsinki. All patients provided written informed consent for personal data analysis for research purposes.

2.2. Study Design

We describe a multicentric retrospective study evaluating outcomes in patients aged 18–59 years who underwent frontline treatment with BV + AVD for advanced stage cHL, in secondary and tertiary oncology centers in Italy. A predefined minimum sample size of ≥ 143 patients was required to ensure adequate representation for PFS analysis. This target was selected to provide the largest real‐life cohort of patients aged ≥ 18 and < 60 years reported to date in the literature, as previous retrospective series have included between 10 and 142 cases in this age group [28, 29, 30, 31, 32]. Moreover, a median follow‐up of at least 24 months was required to assess the PFS Kaplan–Meier curve plateau as reported in the ECHELON‐1 trial [5, 8, 9, 10]. The observation period used in the study was adjusted accordingly to meet these two study design requirements. The primary objective was to evaluate specifically in a real‐life setting the PFS in patients aged 18–59 years treated with BV + AVD, a monoclonal antibody–drug conjugate‐based regimen omitting bleomycin, with its pharmacokinetic and pharmacodynamic advantages in terms of efficacy. Secondary objectives were the dose‐density and dose‐intensity of the BV + AVD regimen, the rate of complete metabolic remission (CMR) at end‐of‐treatment (EoT), and the hematologic and extra‐hematologic toxicity profile.

2.3. Data Collection

We collected data from medical records and/or local databases on consecutive Ya&A with stage III/IV cHL (Supporting Information methods: Data Collection) treated with frontline BV + AVD, as per ECHELON‐1 protocol (Supporting Information methods: BV + AVD Treatment Plan) [5, 8, 9, 10]. We also acquired data on additional therapies, including radiotherapy to RNMs (Supporting Information methods: Irradiation) [33, 34, 35], which patients received if needed.

2.4. Definitions

PFS was defined as the time from day 1 of BV + AVD first dose to the earliest of the following events: a non‐complete response following the scheduled frontline anticancer treatment, that is, BV + AVD, relapse at any time, death from any cause or last follow‐up visit (censoring).

Dose‐density and dose‐intensity of BV + AVD regimen were defined as: (total dose given/planned)/(cycle days observed/planned).

CMR at EoT was assessed by using FDG‐PET scan interpreted with the Deauville Scale (DS) 5‐point scoring system [36, 37, 38, 39, 40] (Supporting Information methods: FDG‐PET Assessments).

Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

2.5. Inclusion and Exclusion Criteria

We included in the analysis patients 18–59 years old with a histological diagnosis of cHL receiving as frontline therapy at least one BV + AVD course. Additional inclusion criteria were Ann Arbor stages III–IV, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–3, left ventricular ejection fraction (LVEF) ≥ 50% regardless of global systolic longitudinal myocardial strain (GLS) at echocardiographic assessment. Patients with baseline comorbidities such as diabetes mellitus, hepatitis B virus (HBV) infection, and/or human immunodeficiency virus (HIV) positivity were also eligible for inclusion.

Patients were excluded from the analysis if they had major comorbid conditions at baseline (such as creatinine clearance < 35 mL/min, serum transaminases more than four times the normal value, total bilirubin > 3.5 mg/dL, and recent myocardial infarction [within 3 months prior to BV + AVD start]).

2.6. Adverse Event Evaluations

In the event of neutropenic fever, all patients underwent detailed clinical evaluation, full blood tests, and paired blood cultures drawn from both central venous access and peripheral vein for cultures (10 mL of blood per bottle; signal system, Oxoid, Hants, UK) repeated every 72 h until fever resolution, as already described (Supporting Information methods: Infection Diagnostic Work‐up) [41, 42].

Neurological signs and symptoms (including incidence, grade, distribution, medications used for treatment, and status at last follow‐up) were evaluated by using neurological examinations (Supporting Information methods: Neurological Assessment).

Patients were scheduled to undergo baseline and serial cardiac evaluations: 2D echocardiography, and speckle tracking echocardiography at baseline, interim, EoT and within 6 months from the end of all antineoplastic treatments, as already reported [25, 26, 27]. Clinical cardiologist experts in echocardiography analyzed each study for standard echocardiography and strain measurements (Supporting Information methods: Cardiology Assessment) [43].

2.7. Statistical Analysis

The Kaplan–Meier method was used to estimate PFS, and the differences in PFS between groups were evaluated using the log‐rank test. The median follow‐up time was calculated using the reverse Kaplan–Meier method. A univariable Cox proportional hazards model was fitted to assess the associations between continuous covariates and PFS. Cox regression analysis was used to estimate the hazard ratio (HR) and the 95% CI for the treatment effect on PFS. Stratification factors included several baseline variables (Supporting Information methods: Statistical Analysis). Differences between groups were tested by the log‐rank test, and Student's t test. Descriptive statistics were calculated, including mean, standard deviation, median, and range for continuous variables, and frequency counts and percentages for categorical variables. The association between categorical variables was evaluated using the χ ² or Fisher exact test, and differences in a continuous variable between patient groups were assessed using the Mann–Whitney test. The p value for statistical significance was set at 0.05 for all evaluations. Statistical analysis was performed using R software (version 4.1).

3. Results

3.1. Patient Characteristics

A total of 150 patients aged 18–59 years who were expected to receive six cycles of BV + AVD for newly diagnosed advanced stage cHL were identified from November 1, 2021 to December 31, 2024, with follow‐up to April 2025.

Patient characteristics are shown in Table 1. Eighty‐one patients (54%) were male. The median age was 32 years, with the majority (100, 70%) of patients aged between 18 and 45 years, and a minority of patients aged over 45 years. ECOG PS was 0–2 in about 90% of patients. Histologically, nodular sclerosis was observed in 83% (125/150) of patients. A total of 127 patients (84.7%) had stage IV disease, and 23 patients (15.3%) had stage III disease with localized extra‐nodal involvement. The invasion of spleen, bone, lung, and/or liver was in 56 (37%), 90 (60%), 53 (35%), and 15 (10%) patients, respectively. A quarter of patients had > 1 extra‐nodal site involved. B symptoms were present in 90 patients (60%). Fifty‐seven (38%) patients had large nodal masses. Overall, 25% (38/150) of patients had a high‐risk international prognostic score (IPS) of 4 to 7.

TABLE 1.

Patients' characteristics at baseline.

Characteristic	Total
Number of patients	150 (100%)
Male sex	81 (54%)
Age, median (range) years	32.6 (18–59)
≤ 45years	100 (70%)
> 45 years	50 (30%)
ECOG PS ≤ 2	136 (90.7%)
ECOG PS > 2	14 (9.3%)
cHL histological subtype
NS	125 (83.3%)
MC	12 (8%)
LR	9 (6%)
LD	4 (2.7%)
Ann Arbor stage
III	23 (15.3%)
IV	127 (84.7%)
Number of nodal sites involved
Median (range)	12 (3–21)
Spleen involvement	56 (37.3%)
Extranodal involvement
Bone	90 (60%)
Lung	53 (35.3%)
Liver	15 (10%)
Other	18 (12%)
Large nodal mass	57 (38%)
B symptoms	90 (60%)
IPS < 4	113 (75%)
IPS ≥ 4	37 (25%)
Comorbidities a
Pulmonary	50 (30%)
Cardiac	50 (30%)
Type 2 diabetes	41 (27.3%)
Hepatic	12 (8%)
HIV positive	3 (2%)
Peripheral neuropathy b	30 (20%)
Previous history of malignancy c	12 (8%)

Note: Values are n (%) unless otherwise specified. Ann Arbor staging: stage III, defined as multiple lymph node groups on both sides of the diaphragm; stage IV, defined as multiple extra‐nodal sites or lymph nodes and extra‐nodal disease; B symptoms: fever, weight loss > 10% in the last 6 months, and/or nocturnal sweat; Large nodal mass, defined as lymph node mass with a long axis > 7.5 cm. Pulmonary comorbidities: mild to moderate reduction in diffusing capacity of the lungs for carbon monoxide (DLCO) and/or chronic obstructive pulmonary disease due to tobacco use. Cardiac comorbidities: hypertension, history of heart disease, coronary artery disease, atrial fibrillation, and/or heart transplanted for cardiomyopathies. Hepatic comorbidities: hepatitis B virus infection, hepatitis C virus infection or auto‐immune hepatitis.

Abbreviations: cHL = classical Hodgkin lymphoma; ECOG PS: Eastern Cooperative Group Performance Status (ECOG 3: patients were capable of limited self‐care, confined to bed or chair more than 50% of time); HIV = Human immunodeficiency virus; IPS: international prognostic score, including age, sex, stage, hemoglobin level, albumin level, lymphocyte count and white blood cell count; LD = lymphocyte‐depleted subtype; LR = lymphocyte‐rich subtype; MC = mixed cellularity subtype; NS = nodular sclerosis subtype.

^a Some patients had more than one comorbidity simultaneously, and about 30% of these would not have met the inclusion criteria for the ECHELON‐1 trial.

^b None of these patients suffered from grade > 2 peripheral neuropathy.

^c Previous history of malignancy includes three patients with breast cancer undergoing surgery and localized radiotherapy, three patients with papillary thyroid carcinoma undergoing surgery ± radioiodine therapy, two patients with colon cancer undergoing surgery and chemotherapy, one patient with hepatocellular carcinoma undergoing surgery, one patient with non‐small cell lung cancer undergoing surgery and chemotherapy, one patient with cervical carcinoma undergoing surgery, and finally one patient with melanoma undergoing surgery.

As comorbidities, 50 patients (30%) had lung abnormalities (mild to moderate reduction in diffusing capacity of the lungs for carbon monoxide [DLCO] and/or chronic obstructive pulmonary disease) due to tobacco use, 50 patients (30%) had cardiovascular diseases (hypertension, N = 38; atrial fibrillation, N = 8; coronary artery disease, N = 6; and/or heart transplantation for cardiomyopathies, N = 2). Preexisting neuropathy due to diabetes mellitus was observed in 30 patients (20%), although none had neuropathy > grade 2 at baseline. Twelve patients (8%) had liver abnormalities (HBV infection in eight patients; autoimmune hepatitis in three; hepatitis C virus infection in one), and three patients (2%) had HIV infection. Twelve patients (8%) had a previous history of other malignancies.

Approximately one‐third of the patients presented with at least one of the above comorbidities that would have made them ineligible for the ECHELON‐1 trial [5].

3.2. BV + AVD in Ya&A in Real‐Life: Treatment Delivery, Dose‐Density/Dose‐Intensity

Dose‐density/dose‐intensity data were available for all 150 cases. Overall, 147 out of 150 patients (98%) completed six courses of BV + AVD; the remaining three patients died from infection (N = 2) after two courses of BV + AVD respectively, and from gastro‐intestinal toxicity (N = 1) after three courses of BV + AVD. The median number of courses received was six (range, 2–6). The median relative dose‐intensity for the overall patient population was 100%, with a range of 12%–100%. The median duration of the BV + AVD regimen was 169 days (range, 56–203 days), matching the expected duration of 168 days. In particular, 9% (N = 13) of patients received < 85% of the planned total dose of BV, that is, a median dose‐intensity for the entire population of 81.2 mg every 2 weeks; 3% (N = 4) of patients received < 85% of the planned total dose of doxorubicin, that is, a median dose‐intensity for the entire population of 47 mg every 2 weeks; 11% (N = 16) of patients received < 85% of the planned total dose of vinblastine, that is, a median dose‐intensity for the entire population of 11.4 mg every 2 weeks; finally, 8% (N = 12) of patients received < 85% of the planned total dose of dacarbazine, that is, a median dose‐intensity for the entire population of 704 mg every 2 weeks. Overall, regarding the relative dose‐intensity of the planned BV + AVD regimen, 105 patients (70%) received the full dose, 29 patients (19%) received a dose intensity between 85% and 99%, while 16 patients (11%) received a dose reduction of > 15%. There was no statistically significant difference (p = 0.92) in the median age between patients receiving dose intensity < 85% and those receiving dose intensity ≥ 85% (median age of 32 years [range, 23–59 years] in the group with dose intensity < 85% vs. 37 years [range, 18–60 years] in the group with dose intensity ≥ 85%).

3.3. BV + AVD in Ya&A in Real‐Life: EoT Responses

Overall, 147 out of 150 patients (98%) underwent EoT FDG‐PET examinations after six BV + AVD cycles, whereas three patients did not due to toxicity (deaths from septic shock [N = 1 case], COVID infection [N = 1 case], and paralytic ileus [N = 1 case]) during BV + AVD treatment. Excluding these cases, all patients were assessable for the final metabolic response. Altogether, the analysis of EoT FDG‐PET scans assigned a DS score as follows: DS score 1 to 110 patients, DS score 2 to 15 patients, DS score 3 to 15 patients, DS score 4 to four patients, and DS score 5 to three patients. Overall, the complete response rate at EoT was 93.3% (95% CI, 88.1%–96.8%). In fact, considering the global outcome of the 150 patients who received at least one BV + AVD course, 140 patients obtained CMR, four patients resulted in residual disease with partial metabolic remission, three patients were primary refractory (DS score 5), and three patients discontinued treatment early (during induction therapy) due to death from acute toxicity.

3.4. BV + AVD in Ya&A in Real‐Life: Outcome

The median follow‐up for the entire series of 150 patients was 24 months with a range of 2–42 months. Overall, there were 13 events (Table S1). Three patients died during induction therapy: one from sepsis due to Pseudomonas aeruginosa , one from COVID‐19 infection, and one from paralytic ileus. Ten patients had persistent lymphoma during the observation period. Following BV + AVD, based on EoT FDG‐PET assessments, four patients had residual disease with partial metabolic response, and three patients had primary refractory disease. In addition, at a median follow‐up of 16 months (range, 12–17 months), three patients had relapsed disease. The salvage treatments were the following: four out of 57 (7%) patients who were potential candidates for consolidative radiotherapy due to large nodal disease at baseline underwent treatment, including irradiation of the mediastinal site, targeting RNMs with a long‐axis diameter ≥ 2.5 cm on computed tomography (CT) scans (median: 4 cm; range: 2.5–4.5 cm); the remaining six cases received high‐dose chemotherapy and autologous hematopoietic stem cell transplantation.

3.5. BV + AVD in Ya&A in Real‐Life: PFS

Two‐year PFS for the entire cohort of 150 patients (Figure 2) was 91% (95% CI, 0.864–0.958). Outcomes were similar for the age ≥ 18–≤ 45 year and > 45– ≤ 59 year subgroups with 2‐year PFS of 90.6% (95% CI, 85–96.7) and 91.7% (95% CI, 84.2–99.8), respectively (p = 0.8; Figure 3A), as well as outcomes were similar for the stage III and IV subgroups with 2‐year PFS of 91.3% (95% CI, 80.5–100) and 90.9% (95% CI, 85.9–96.2) respectively (p = 1; Figure 3B). Finally, univariable analyses of predefined subgroups showed that all patients appeared to benefit from BV + AVD (Supporting Information results: Univariable Analysis Results). The main efficacy results of the study treatments are reported in Table 2.

FIGURE 2.

Kaplan–Meier curve of 24‐month progression‐free survival (PFS) of 150 young adults and adults with advanced stage classical Hodgkin lymphoma who received frontline Brentuximab Vedotin plus Adriamycin, Vinblastine, Dacarbazine in real life. Figure also shows number at risk during follow‐up.

FIGURE 3.

(A, B) Progression‐free survival (PFS) in young adults and adults with advanced stage classical Hodgkin lymphoma treated with frontline Brentuximab Vedotin plus Adriamycin, Vinblastine, Dacarbazine in real life. (A) PFS according to age stratification (18–≤ 45 years [N = 100] vs. > 45–59 years [N = 50]). (B) PFS according to stage stratification (stage III [N = 23] vs. stage IV [N = 127]). Figures also show number at risk during follow‐up.

TABLE 2.

The main efficacy results of the study treatment in the entire Ya&A population.

Outcome	All patients (N = 150)
ORR	96% (95% CI: 91.5%–98.5%) (144/150)
CMR	93.3% (95% CI: 88.1%–96.8%) (140/150)
PMR	2.7% (95% CI: 0.7%–6.7%) (4/150)
24‐months PFS	91% (95% CI: 86.4%–95.8%)

Abbreviations: CI, confidence interval; CMR, complete metabolic remission; ORR, overall response rate; PFS, progression free survival; PMR, partial metabolic remission; Ya&A, young adults and adults.

3.6. Supportive Therapy

All patients received supportive care, as described above (Figure 1). The totality of patients underwent primary anti‐infectious prophylaxis with long‐acting granulocyte‐colony stimulating factor (G‐CSF) (median number of cumulative administrations of lipegfilgrastim of 12 vials; range, 4–12 vials), and with trimethoprim sulfamethoxazole and acyclovir. HBV reactivation prophylaxis was administered in five patients with lamivudine (all were HBcAb+/HBsAg−) and in three patients with tenofovir disoproxil fumarate (all were HBsAg+/HBV DNA−). ESAs were administered to 60 patients (40%) with chemotherapy‐associated anemia of grade (G) 1–2. Nineteen patients underwent L‐acetylcarnitine and/or pregabalin administration for G ≥ 2 peripheral neuropathy. In twenty‐three patients, cardiological toxicity early treatment included angiotensin‐converting enzyme inhibitors (5 cases), angiotensin receptor blockers (6 cases), beta‐blockers (8 cases), and/or anti‐arythmic drugs (4 cases).

3.7. Adverse Events

The safety profiles of BV + AVD in Ya&A are summarized in Table 3. Regarding hematological toxicity, a total of eight patients (5%) reported at least one neutropenic event of G 3; and eight patients (5%) reported anemia of G 3. All‐grade peripheral neuropathy occurred in 29% of patients, including G ≥ 2 peripheral neuropathy in 13% of them. The median age of the patients experiencing G ≥ 2 peripheral neuropathy was higher than that of those with G < 2 peripheral neuropathy (42 vs. 31 years, respectively; p = 0.0035). Infections of G ≥ 3 occurred in 8 patients (5%) as febrile neutropenia (G 3, in five patients), and as septic shock (G 5), COVID infection (G 5), and upper respiratory tract infection (G 3) in one patient each. Three patients (2%) reported G 4 (N = 2) and G 5 (N = 1) gastrointestinal toxicity (paralytic ileus); four patients presented elevation of alanine‐amino transferase (G 2).

TABLE 3.

Safety results in the entire series of Ya&A undergoing BV + AVD in real‐life, stratified according to the grades of CTCAE.

Variable	Total, N (%)	Grade 1,  N (%)	Grade ≥ 2, N (%)
Num. of patients	150 (100)	84 (56)	38 (25)
Hematological toxicity
Anemia	60 (40)	39 (26)	21 (14)
Neutropenia	49 (33)	41 (27)	8 (5)
Neurological toxicity
Peripheral neuropathy	43 (29)	24 (16)	19 (13)
Infectious toxicity
Febrile neutropenia	5 (3)	N/A	5 (3)
Bronchial infection	1 (< 1)	N/A	1 (< 1)
Pneumonia (COVID‐19)	1 (< 1)	N/A	1 (< 1) a
Sepsis	1 (< 1)	N/A	1 (< 1) a
Gastrointestinal toxicity
Nausea	60 (40)	43 (29)	17 (11)
Constipation	41 (27)	31 (20)	10 (7) b
Dyspepsia	38 (25)	38 (25)	0
Alanine aminotransferase increase	15 (10)	11 (7)	4 (3)
Extra‐hematological toxicity
Fatigue	104 (69)	84 (56)	20 (13)
Flushing	5 (3)	5 (3)	0
Cardiac toxicity
Heart failure	19 (13)	10 (7)	9 (6)
Atrial fibrillation	4 (3)	2 (1)	2 (1)

Note: All side effects possibly related to BV + AVD treatment were reported according to the common terminology criteria for adverse events (CTCAE).

Abbreviations: BV + AVD = Brentuximab Vedotin, Adriamycin, Velbe, Dacarbazine; Ya&A = young adults and adults.

^a Grade 5 toxicity.

^b One patient died from paralytic ileus (grade 5).

Overall, cardiotoxicity of any grade according to the common terminology criteria for adverse events (CTCAE) was observed in 23 out of 150 patients (15.3%). From the perspective of cardiac toxicity, and specifically for the assessment of heart failure, we referred to the 2022 ESC Cardio‐Oncology Guidelines [27]. According to these criteria, a complete echocardiographic evaluation—including GLS and LVEF at baseline, interim, EoT, and 6 months post‐treatment—was available for 59 patients (39%). Among these, six patients (10%) showed a ≥ 15% reduction in GLS from baseline (Figure S1A), and three patients (5%) experienced a ≥ 10% decrease in LVEF (Figure S1B). Normal thresholds were defined as GLS ≥ −20% and LVEF ≥ 50%. Among the remaining 91 patients, who had at least two echocardiographic evaluations (baseline and EoT), a grade 1 reduction in myocardial strain was observed in 10 patients. Additionally, two patients experienced relapse of atrial fibrillation (grade 3), both of which were resolved completely with medical management.

Cumulatively, only three (2%) out of 150 patients discontinued study treatment permanently due to G 5 toxic events (as above reported). Aside from 15 cases with at least 1 emergency department visit (median, 1 visit [range, 1–5]), with a median duration of hospital stay of 1.5 days (range, 1–5 days), no other patients required hospitalization due to treatment‐related adverse events.

4. Discussion

The vast majority of patients referred to cancer centers for cHL care are 18–59 years aged [1]; in this age setting, the disease is frequently diagnosed with extranodal involvement, bulky lymph nodes and/or B symptoms, that is, with more extensive than limited stage [1]. About one‐third of these patients do not benefit from up‐front therapy with the ABVD regimen [5]. In this age setting, the decision‐making on the most appropriate therapy is a relevant issue in clinical practice. According to an updated review of the scientific literature, alternative frontline therapeutic strategies include the administration of novel regimens based on selectively active agents. Several controlled studies have been published with contradictory results [3, 4]. For instance, in the phase III HD21 trial, in patients aged < 60 years up‐front BV in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) in stage II/IV c‐HL demonstrated a 4‐year PFS of 94% [4]. However, after the end of the BrECADD regimen, consolidative radiotherapy was given in 15% of patients for PET‐positive (DS scores 4 and 5) RNM with a long axis ≥ 2.5 cm at CT scans. In this trial, 42% of patients experienced grade 3 to 4 treatment‐related adverse events, and consequently discontinuations and/or emergency department visits were mostly for febrile neutropenia and thrombocytopenia [4]. A phase III randomized trial (SWOG S1826) examining the frontline use of nivolumab in combination with Adriamycin, Vinblastine, and Dacarbazine (N‐AVD) in patients with advanced‐stage cHL, now closed to enrollment with 2‐year PFS data reported and longer follow‐up ongoing, showed improved PFS in the N‐AVD arm compared to the BV + AVD arm (NCT03907488) [3]. However, in Ya&A the Kaplan–Meier curve of the PFS of N‐AVD steadily declines over time until it aligns with that of BV + AVD. Noteworthy, at 2 years this last curve flattened out with a plateau that constantly remained at 86% [3]. Follow‐up of the patients aged 18–59 years in the N‐AVD arm is too short. More insight into the safety and efficacy of these combinations will likely be provided in the next years. Thus, all these approaches are not routinely employed in most countries because they have not been clearly proven effective, safe, and/or economically advantageous [6, 7].

Our study, based on the largest real‐life series of patients aged 18–59 years with high‐risk cHL provides clear evidence of the efficacy of the upfront BV + AVD regimen for six cycles, as reflected by a substantial increase in the number of survived patients in CMR without further antineoplastic therapy. The 85% of our patients had stage IV disease, and a quarter had more than one extra‐nodal site involved and/or high IPS, corresponding with worse prognosis. In this non‐trial clinical context, the 2‐year PFS rate was 91% (95% CI, 0.864–0.958), without consolidation radiotherapy on initial bulky sites and/or RNMs. The treatment was effective across all Ya&A with advanced stage cHL, regardless of the pre‐specified risk factor sub‐group; for example, the treatment was equally effective in patients aged 18–45 years versus those aged > 45–59 years, and in stage III versus stage IV disease (Supporting Information results: Univariable Analysis Results). These findings are of notable clinical interest, as they demonstrate an absolute improvement of at least 5 percentage points in outcome compared with the Ya&A population in the original ECHELON‐1 trial [5, 8, 9, 10, 11]. Noteworthy, at baseline about one‐third of our patients presented with unfavorable prognostic factors that would have rendered them ineligible for the pivotal ECHELON‐1 trial due to one or more exclusion criteria, including preexisting neuropathy (none exceeding grade 2) related to type 2 diabetes (20%), clinically relevant cardiovascular conditions (20%), ECOG performance status > 2 (9%), history of other malignancies (8%), liver abnormalities (2%), and/or HIV infection (2%). We acknowledge that this comparison with the ECHELON‐1 trial data is approximate, as it is based on the authors' extrapolation from available trial reports [5, 8, 9, 10, 11].

Three main findings of our study warrant attention, as they may explain the therapeutic success of this strategy. First, the use of broad‐spectrum supportive care measures played a crucial role in ensuring treatment tolerability and effectiveness. This included antimicrobial prophylaxis with trimethoprim‐sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia, acyclovir to prevent herpesvirus reactivation, and nucleos(t)ide analogues in patients with evidence of HBV infection, in line with established recommendations [42]. In addition, all patients underwent comprehensive monitoring throughout treatment, including regular clinical evaluations, laboratory testing (with a focus on hematologic, hepatic, and renal parameters), and radiologic surveillance. Such a structured monitoring strategy enabled early detection and prompt management of adverse events and was implemented according to international guidelines for patients receiving curative‐intent chemotherapy [14, 22, 23, 24, 42, 43]. Robust primary prophylaxis with long‐acting recombinant G‐CSF, namely lipegfilgrastim, and ESA, such as epoetin α, allowed for near‐complete maintenance of chemotherapy dose intensity [14, 42]. Lipegfilgrastim, approved by the EMA in 2013, has shown superior pharmacokinetics compared to pegfilgrastim, with nearly 50% higher area under the curve (AUC) in a phase III trial [44], and shorter neutrophil recovery times in a meta‐analysis [45]. In our cohort, this supportive strategy ensured a median dose intensity of 100%, likely contributing to the high complete remission rates and favorable PFS observed, outperforming outcomes from the ECHELON‐1 trial. This multifaceted supportive approach was particularly important given the high proportion of patients with baseline comorbidities, such as cardiovascular disease, pulmonary impairment, and viral infections, who would have otherwise been excluded from registration trials. Second, FDG‐PET image quality assessment using 68Ge phantom calibration—performed by both participating nuclear medicine units—contributed to image accuracy and reproducibility. This technique improves PET scanner qualification, reduces technical variability, and enhances FDG‐PET precision [15, 16, 17]. Finally, our study provides evidence that secondary and tertiary cancer centers dedicated to lymphoma management, offering structured interdisciplinary care, may enhance survival outcomes for stage III/IV cHL patients treated with BV + AVD. Thanks to this comprehensive supportive care approach, full‐dose chemotherapy could be administered as planned in nearly all patients, with a median dose intensity of 100%. This optimal treatment delivery likely contributed to the high complete remission rates and superior PFS observed in our cohort, as compared with the ECHELON‐1 trial [5].

In our study, BV + AVD was well‐tolerated. Overall, the rate of G ≥ 3 toxicity was 22%. There were 33 adverse events (in a total of 33 patients) of G ≥ 3 of which only three (9%, 3/33) were fatal; the remaining 30 events were all reversible by medical management and did not require hospitalization in approximately 70% of cases. In addition, advanced echocardiographic techniques performed by expert echocardiographers (for exploring subclinical signs of impaired ventricular function, i.e., strain rate imaging with measures of global radial and circumferential strain) of the cardio‐oncology team [43] documented preserved myocardial ventricular function in most of the systematically evaluated cases up to 6 months after therapy.

Our study has some limitations. First, up‐front therapy with BV + AVD with primary anti‐infectious prophylaxis and vigorous supportive care including early neurologic and cardiologic therapy is not cost‐effective compared to the standard approach. However, our strategy relevantly reduces the number of patients unable to receive curative‐intent antineoplastic therapy. In our series, despite the presence of multiple comorbidities and/or poor ECOG PS, we treated a vast majority of patients, using the BV + AVD regimen at standard doses without delays. In our hands, early use of L‐acetylcarnitine and/or pregabalin and tailored vinblastine dosage reduction were critical to preventing worsening peripheral neuropathy (and subsequent BV dosage reduction); likewise, early introduction of angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, beta‐blockers, and/or antiarrhythmic medication based on strict echocardiographic monitoring [43] was key to minimizing cardiovascular toxicity [25, 26, 27]. Additional major limitations include the retrospective nature of the study, and short follow‐up without data on late toxicity of BV + AVD in real life, in particular anthracycline‐induced cardiac toxicity.

In conclusion, our multi‐center, non‐controlled, real‐life study including the largest series of Ya&A with high‐risk cHL to date, provides compelling evidence that up‐front treatment with six cycles of BV + AVD without additional antineoplastic treatment, including, consolidation radiotherapy, is safe and effective in this population. Patients aged ≥ 18 and < 60 years are most likely to benefit when treated in a cancer hospital specialized in HL care with dedicated programs, robust supportive treatments and certified FDG‐PET imaging protocols [14, 15, 16, 17, 43]. This information should be widely shared among patients, referring physicians, and healthcare policy makers.

Author Contributions

Marco Picardi: conceptualization, data curation, investigation, methodology, project administration, supervision, visualization, writing – original draft preparation, review and editing. Claudia Giordano, Annamaria Vincenzi, and Novella Pugliese: formal analysis, data curation, investigation, writing – original draft preparation, review and editing. Alessia Scarpa, Assunta Lombardi, Elena Vigliar, Giancarlo Troncone, Rosaria Cappiello, Massimo Mascolo, Giovanni Esposito, Maria Prastaro, Ciro Santoro, Roberta Esposito, Carlo Gabriele Tocchetti, Ciro Mainolfi, Rosa Fonti, Silvana Del Vecchio, Fabio Trastulli, Maria Annunziata, Rossella Iula, Catello Califano, Marianna Carchia, Marcello Persico, Alessia Salemme, Emanuele Nicolai, Andrea Soricelli, and Marco Salvatore: data curation, investigation, writing – review and editing. Fabrizio Pane: conceptualization, data curation, investigation, methodology, supervision, writing – original draft preparation, review and editing.

Ethics Statement

All necessary approvals were obtained by the local ethics committee (Campania 3 approval protocol number: 61/2025). The study was undertaken in accordance with the Declaration of Helsinki. All patients provided written informed consent for personal data analysis for research purposes.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1: ejh70060‐sup‐000‐Data.odt.

Figure S1: ejh70060‐sup‐000‐FigureS1.pdf.

Table S1: Characteristics of Ya&A with refractory or relapsed classical Hodgkin lymphoma following first‐line BV + AVD regimen.

Picardi M., Vincenzi A., Giordano C., et al., “Brentuximab Vedotin With Adriamycin, Vinblastine, and Dacarbazine for Patients Aged 18–59 Years With Untreated Advanced Stage Classical Hodgkin Lymphoma: The Largest Real‐Life Series From Southern Italy Cancer Centers,” European Journal of Haematology 116, no. 2 (2026): 174–184, 10.1111/ejh.70060.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.