Abstract Hodgkin lymphoma (HL) is a B‐cell‐derived malignancy often affecting young adults. Allocation into risk groups is based on staging with positron emission tomography and computed tomography (PET/CT) and the presence or absence of risk factors. Standard treatment for early‐stage favorable classic HL (cHL) consists of two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), followed by 20 Gy involved‐site radiotherapy (IS‐RT). Two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) or a procarbazine‐free eBEACOPP variant plus two cycles of ABVD, followed by 30 Gy IS‐RT in the case of PET/CT positivity and no further treatment in the case of PET/CT negativity after chemotherapy should be considered in patients with early‐stage unfavorable cHL ≤ 60 years. If a less intensive approach is preferred and in individuals > 60 years, four cycles of A(B)VD followed by 30 Gy IS‐RT can be given. In advanced cHL, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) for four (in the case of PET/CT negativity after two cycles) or six cycles (in the case of PET/CT positivity after two cycles), followed by PET/CT‐guided 30 Gy IS‐RT should be considered in patients ≤ 60 years. Six cycles of nivolumab and AVD (N‐AVD) followed by PET/CT‐guided 30 Gy IS‐RT represents a less intensive alternative for younger patients and the preferred approach for patients > 60 years. Patients with cHL recurrence should receive checkpoint inhibitor‐containing salvage treatment followed by high‐dose chemotherapy and autologous stem cell transplantation if eligible. Treatment of nodular lymphocyte‐predominant HL differs from cHL in some situations and may contain an anti‐CD20 antibody. This guideline aims at providing recommendations for diagnosis, staging, treatment, and follow‐up of HL.

During the pre-Omicron phases of the COVID-19 pandemic, patients with hematological neoplasms were characterized by very high morbidity and mortality rates. Remdesivir, a viral RNA-polymerase inhibitor, interferes with key SARS-CoV-2 enzymes, preventing the virus from multiplying. The use of convalescent plasma (CP) in treating patients with COVID-19 has been shown to be beneficial in patients with an impaired humoral response to infection, including most of those on active treatment for hematologic malignancies. This retrospective, non-interventional study was performed using the Croatian Cooperative Group for Hematological Diseases database of patients with hematological malignancies infected with SARS-CoV-2. Patients treated with remdesivir and/or CP were matched to those untreated according to age, disease type, and antineoplastic therapy. We identified 119 patients treated with remdesivir and/or CP fulfilling entry criteria and matched 116 according to our established criteria to one of the 374 untreated patients. Treatment significantly reduced COVID-19 mortality. The beneficial effect of antiviral therapy was limited to those who started antiviral treatment within 7 days of the onset of symptoms. Due to the exclusive enrolment of hematological patients with COVID-19, our study provides unique insights into the benefits of early application of both antiviral and CP therapy. It emphasizes the need for early administration before the infection has transformed into the hyperinflammatory phase.

BackgroundIbrutinib is effective for B-cell malignancies but is associated with cardiovascular adverse events, including atrial fibrillation (AF) and hypertension. Longitudinal data on left atrial (LA) remodeling during treatment are limited. We characterized serial changes in LA size and function during chronic ibrutinib therapy.MethodsIn this prospective observational cohort, 40 patients starting ibrutinib underwent clinical assessment, 24–72-hour Holter monitoring, and echocardiography with LA strain at baseline and 3, 6, 12, and long-term (nominal 36-month) follow-up. Primary analyses used observed paired data, random-intercept mixed models, standardized response means (SRMs), and Benjamini-Hochberg adjustment across 24 primary contrasts.ResultsMedian age was 65 years and 53% were female. Paired mean LAVI changes were +1.52 mL/m² at 3 months (n = 38), +1.68 at 6 months (n = 36), +2.62 at 12 months (n = 33), and +2.15 at long-term follow-up (n = 31; all q ≤ 0.020). LA reservoir strain worsened from 6 months onward (all q ≤ 0.031), while LA contractile strain, LA lateral-wall TDI, and LV GLS worsened at every follow-up (all q ≤ 0.009). Results were materially unchanged after adjustment for time-varying hypertension and in complete-case sensitivity analyses. Incident AF occurred in 5/40 patients (12.5%; 95% CI 5.5%–26.1%).ConclusionDuring chronic ibrutinib therapy, longitudinal imaging showed modest LA enlargement and consistent deterioration in several LA deformation indices. These treatment-associated observations require confirmation in controlled cohorts.Clinical trial registrationClinicalTrials.gov, identifier NCT03751410.

Tumour bulk is an established prognostic factor in Hodgkin lymphoma (HL) but most patients with limited-stage (LS) HL do not have 'bulk' by standard binary definitions. In the RAPID trial, maximum tumor diameter (MTD) was associated with risk of relapse for LS-HL patients achieving PET-negativity after ABVD chemotherapy. We aimed to externally validate these findings in the H10 trial. Patients with stage I/IIA HL, without mediastinal bulk, who achieved PET-negativity with ABVD were included. 'PET-negative' patients received 3x ABVD plus radiotherapy (n=208) or 3x ABVD alone (n=211) in RAPID, and 3-4x ABVD plus radiotherapy (n=556) or 4-6x ABVD alone (n=303) in H10. Baseline MTD was measured by CT. MTD was strongly associated with event-free survival (relapse or HL-related death) in H10 (HR=1.22, 95%CI:1.07-1.38, p=0.003), a similar effect to the RAPID trial (HR=1.19, 95%CI:1.02-1.39, p=0.02), giving an estimated 21% increase in HL-risk per centimetre MTD (HRpooled=1.21, 95%CI:1.09-1.33, p<0.001). Findings were consistent when adjusting for baseline risk stratification and chemotherapy cycles. The effect sizes were similar for patients treated with chemotherapy alone (HRpooled=1.19, 95%CI:1.01-1.35, p=0.005) and combined modality treatment (ABVD plus radiotherapy; HRpooled=1.24, 95%CI:1.05-1.46, p=0.009) with no evidence of a differential effect (pinteraction=0.97). Treatment modality and MTD were independent risk factors; patients with higher MTD receiving chemotherapy alone had the greatest risk of relapse. This international validation study confirms that MTD is strongly associated with the risk of relapse for LS-HL patients achieving PET-negativity. These findings refine assessment of risk in LS-HL and can inform clinical discussions for risk-adapted application of radiotherapy. NCT00943423 and NCT00433433

Introduction: Current treatment strategy for HIV-associated Burkitt lymphoma (BL) typically rely on intensive chemotherapy regimens modeled on anti-leukemia protocols such as GMALL, LMB, and their regional derivatives. These are often resource-intensive, prolonged, and associated with dose-limiting toxicities, frequent interruptions, and high treatment-related mortality. The “CARMEN” protocol is a dose-dense regimen developed to improve tolerability while maintaining efficacy [Ferreri, Blood Adv 2022]. It includes a 36-day, single-course induction with weekly sequential doses of six anticancer drugs, plus intrathecal chemo, followed by high-dose cytarabine–based consolidation. Favorable safety and efficacy profiles with CARMEN and similar regimens have helped narrow the outcome gap between HIV-pos and HIV-neg patients (pts) with BL. However, systematic comparisons of efficacy across chemo regimens—particularly when stratified by prognostic scores—remain limited. In the absence of feasible prospective comparative trials, the HIV Lymphoma Network of the European Hematology Association launched an international study to assess feasibility and efficacy of GMALL (and its derivatives), CARMEN, and other regimens in HIV-pos pts with BL treated at 19 centers across Germany, Italy, Spain, France, and Croatia. Methods: HIV-pos adults with BL treated between 2005–2024 were included. All pts were eligible regardless of ECOG PS, stage, IPI, BLIPI [Olszewski, JCO 2021], or treatment. Pts with HBV/HCV infection were included; those lost to follow-up within 6 months of diagnosis were excluded. The primary endpoint was overall survival (OS), analyzed by treatment regimen and stratified by IPI (low: 0–1; intermediate: 2–3; high: 4–5) and BLIPI (low: 0; intermediate: 1; high: 2–4). Feasibility and tolerability were assessed by the incidence of treatment-related deaths, dose reductions or interruptions, grade ≥3 non-hematologic toxicities, and grade ≥3 infections. Variables significantly associated with OS were further evaluated using Cox proportional hazards models. Results: Of 247 consecutive HIV-pos pts with BL (median age 43; range 25–68; 227 males), 16 were excluded for early loss to follow-up, leaving 231 for analysis. Of these, 145 received GMALL or derivatives (BFM, BURKIMAB), 41 received CARMEN, 16 received LMB, and 20 received R-CHOP. Nine pts treated with other regimens were excluded from analyses. Baseline characteristics were comparable across groups, except for B symptoms, which were not recorded in the LMB cohort. At a median follow-up of 65 months (range 7–164), 73 pts experienced a PFS event, and 61 died: 41 from lymphoma, 17 from infections, and 2 from second cancers. The 5-yr PFS and OS were 70% (95%CI:69–71) and 71% (95%CI:70–72), respectively. Stratified by treatment regimen, 5-yr OS was 74% (95%CI:73–75) for GMALL and derivatives, 68% (95%CI:66–70) for CARMEN, 79% (95%CI:78–80) for LMB, and 45% (95%CI:25–62) for R-CHOP. IPI data were available for 212 pts (95%). Among 49 with IPI 0–1, only two events occurred, with a 5-yr OS of 95% (95%CI:94–96) and no significant differences across regimens. Among 163 pts with IPI 2–5, the 5-yr OS was 65% (95%CI:64–66), with comparable efficacy among GMALL and derivatives, CARMEN, and LMB, but significantly worse outcomes for R-CHOP. Similar findings were observed using BLIPI stratification. Multivariable analysis identified bulky disease, HIV-RNA levels, gender, and IPI as independent OS predictors. Notably, it confirmed equivalent efficacy among intensified regimens and their superiority over R-CHOP. In terms of feasibility, CARMEN had the most favorable profile: only 5 pts (12%) required dose reductions and 2 (5%) discontinued treatment due to toxicity. In comparison, dose reductions and discontinuations occurred in 30% and 16% of pts on GMALL, and 38% and 16% with LMB. Conclusions: OS rates are encouraging in HIV-pos pts with BL; however, nearly one-third of deaths are still attributable to iatrogenic toxicity. Despite the limitations of a retrospective design, our findings suggest that CARMEN regimen provides outcomes comparable to those of standard intensive protocols (GMALL, its derivatives, and LMB). Efficacy was consistent across all risk subgroups defined by IPI and BLIPI. In addition to its short duration and favorable tolerability, CARMEN may reduce the risk of chronic toxicity and secondary malignancies, owing to its use of single doses of chemotherapeutic agents.

Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by multisystem involvement. Patients can be stratified into an indolent or rapidly progressive disease course. A progressive course warrants early and more aggressive treatment to prevent irreversible organ damage. Therapeutic strategies should be tailored to the presenting symptoms and organ involvement. Autologous hematopoietic stem cell transplantation (AHSCT) has proven to be an effective treatment modality for specific phenotypes of SSc, especially progressive diffuse cutaneous SSc. However, the optimal timing for the transplantation remains unknown. We present two cases of rapidly progressive diffuse cutaneous SSc (dcSSc) treated with AHSCT following inadequate response to conventional immunosuppressive therapy. While both patients experienced significant cutaneous improvement post-AHSCT, internal organ involvement progressed in one case, ultimately resulting in a fatal outcome due to severe sepsis, whereas the second patient remained clinically stable and without immunosuppressive therapy during long-term follow-up. This report contributes to the growing body of evidence supporting AHSCT as a therapeutic option in carefully selected cases of progressive dcSSc. To our knowledge, our cases are the first successful experiences with this treatment modality in Croatia and among the Slavic populations of the Balkan Peninsula, promoting the need for earlier interventions in patients who develop a progressive disease course, particularly with skin involvement.

Advances in understanding the biology of chronic lymphocytic leukaemia (CLL) translated into revolutionary treatments with improved survival outcomes. Consequently, the traditional chemoimmunotherapy courses shifted to targeted therapies, including inhibitors of the Bruton tyrosine kinase (BTKis). BTKis correlate with an increased risk over time of toxicities of the cardiovascular (CV) system, which require proper management. An expert meeting involving 14 haematology and cardiology opinion leaders from 5 Central Eastern European countries was held, aiming to find pragmatic approaches for haematologists to identify the CLL patients at CV risk before starting the BTKis therapy, and further recognize, manage and monitor de novo cardiotoxicities occurring under treatment. Geographical variations have been described, including availability of reimbursed BTKis, national registries, and presence of cardio-oncology units. The experts discussed controversies, unmet needs and potential solutions by exemplifying local challenges and best practices. Each patient requires a personalized strategy based on multiple factors, hence practical pathways to follow during the continuity of care in CLL patients requiring BTKis have been proposed. Rigorous evaluation of the CV risk, periodic assessments of cardiotoxicity during BTKis treatment and work in multidisciplinary teams are vital for managing CV complications without unnecessary interruptions of the CLL treatment.

Mantle cell lymphoma (MCL) is a relatively rare B-cell lymphoma subtype, with a higher incidence among males and a median age of 70 years at diagnosis. MCL is characterized by clinically diverse behavior, from indolent disease to extremely aggressive, related to the presence of biological risk factors such as proliferation rate and TP53 mutations. Most often, patients present with disseminated disease, necessitating systemic treatment. Immunochemotherapy has historically been the mainstay of treatment, but recent data indicate that addition of novel agents, especially covalent Bruton tyrosine kinase inhibitors (cBTKi), may substantially improve outcome in younger and older patients, although a curative approach remains to be shown. In elderly patients, the standard of care is still immuno-chemotherapy such as rituximab-bendamustine, although this may be challenged by non-chemotherapeutic options, such as rituximab plus cBTKi. For patients with relapsed or refractory disease, treatment options are developing rapidly, including CAR-T cell therapy, novel BTK targeting agents, BCL2 inhibitors, and T-cell engagers. In this clinical practice guideline, we present current evidence-based recommendations for diagnosis, staging, treatment, and follow-up of MCL.

From the beginning of the pandemic, people with cancer have experienced a high burden from COVID-19 compared with the general population, both in terms of severe COVID-19-related outcomes and reduced health-related quality of life and mental health. This review presents and discusses expert views on the burden of COVID-19 in individuals with cancer throughout the pandemic. The literature suggests that early in the pandemic, people with cancer had a disproportionately high risk of COVID-19-related hospitalization compared with the general population. This trend continued throughout the pandemic, even after the availability of vaccinations (including boosters) and the emergence of less virulent strains. Rates of hospitalization, intensive care unit admission, and mechanical ventilation varied across studies but were all seen to be higher in people with cancer and COVID-19 compared with the general population or those with cancer alone. Moreover, studies indicated worsened quality of life and mental health in these people during the pandemic and lockdown periods compared with prepandemic or postlockdown periods. Although COVID-19 has entered the endemic phase and is no longer a global health emergency, it remains a significant risk for people with cancer. Generally, COVID-19 continues to increase healthcare resource use, impair mental health, and reduce quality of life in this population, highlighting the need for continued real-world studies. Ongoing research is essential to evaluate the impact of COVID-19 on vaccinated people with cancer, particularly those undergoing systemic cancer therapy who may require continued guidance on preventive measures and treatments to mitigate the risk of severe COVID-19.

Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%-40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.

The characteristics at diagnosis and clinical course of primary extranodal follicular lymphoma (EFL) have not been extensively described. The International Extranodal Lymphoma Study Group (IELSG) conducted an international retrospective survey aimed to describe the clinical features at diagnosis and the outcomes of FL cases with a clinically dominant extranodal component. The dataset included 605 pathologically reviewed cases from 19 different countries, and their outcomes were compared to those of nodal follicular lymphomas. The two most common presentation sites for EFL were the skin (n = 334) and the gastrointestinal tract (n = 72), with 22 cases having primary duodenal localization. These subsets exhibited unique features at diagnosis and significantly different overall survival (OS) patterns. After a median follow-up of 5.5 years, primary cutaneous lymphomas showed a superior outcome [10-year OS: 89% (95% CI, 83%-93%)], while primary gastrointestinal lymphomas had an intermediate outcome [10-year OS: 79% (95% CI, 59%-90%)]. Among the gastrointestinal lymphomas, primary duodenal lymphomas tended toward the best outcome [10-year OS: 95% (95% CI, 69%-99%)]. Other primary extranodal sites had inferior outcomes [10-year OS: 59% (95% CI, 48%-68%)], similar to primary nodal lymphomas [10-year OS: 57% (95% CI, 49%-64%)]. These findings support the identification of specific primary FL localizations as distinct entities with particular clinical and biological characteristics.

Background:The coronavirus disease 2019 (COVID-19) patients with hypogammaglobulinemia who are sick enough to require intensive care unit (ICU) admission exhibit high mortality rates. This study investigates whether the use of rescue hemoadsorption is associated with increased survival and/or improved clinical and biological parameters.Methods:In this prospective study, critically ill COVID-19 patients were consecutively enrolled, and serum protein electrophoresis was used to screen for hypogammaglobulinemia (defined as a gamma-globulin fraction below the 10th percentile and confirmed by a serum IgG level below 700 mg/dL). Twelve patients received hemoadsorption for immunomodulation. The same laboratory parameters were collected from 24 propensity-matched control patients who did not receive hemoadsorption.Results:There was no significant survival difference between patients treated with hemoadsorption and control patients. There was also no significant post-treatment improvement in the clinical parameters or sequential organ failure assessment (SOFA) scores for patients who received hemoadsorption compared to those who did not. Notably, 90% of all patients (32/36) died before day 28, regardless of whether they received hemoadsorption. An independent association between hypogammaglobulinemia and death within 28 days was found for all patients: Hazard ratio (HR) 0.32 (0.15, 0.66), P < 0.001.Conclusion:Hemoadsorption was not associated with increased survival in COVID-19 ICU patients with hypogammaglobulinemia. Our study highlights that a diagnosis of impaired humoral immunity could be a useful clinical predictor of high mortality and of non-response to hemoadsorption for patients with severe COVID-19.

Background/Objectives: Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia but has off-target side effects, most notably cardiac. In order to evaluate the efficacy and toxicity of ibrutinib treatment, risk factors for adverse outcomes and the influence of pretreatment cardiologic evaluation, KroHem collected data on Croatian patients with chronic lymphocytic leukemia treated with this drug. Methods: This is a retrospective survey performed in order to analyze the efficacy and toxicity of ibrutinib in a real-life setting. Patients starting therapy with ibrutinib for chronic lymphocytic leukemia between the time the drug became reimbursable in 2015 and 31 December 2021 were included, irrespective of treatment line. Results: We identified 436 patients fulfilling entry criteria; 404 (92.7%) responded to treatment. Cardiovascular side effects occurred in 25.0% of patients and hemorrhagic in 15.6%. The dose of ibrutinib was permanently reduced in 22.2% of patients. Median follow-up of the cohort was 29 months (IQR 18-41 months), estimated median overall survival 75 months (IQR 36 months-not reached), progression-free survival 54 months (IQR 24-81 months) and time on ibrutinib treatment 44 months (IQR 14-78 months). Factors significantly related to overall survival in multivariate analysis were stage, treatment line and age. Factors significantly related to progression-free survival in multivariate analysis were treatment line, age and pretreatment history or ECG finding of cardiac arrhythmia. Factors significantly related to time on ibrutinib treatment in multivariate analysis were age, pretreatment history or ECG finding of cardiac arrhythmia, and permanent dose reduction for toxicity. Sex, FISH and the presence of arterial hypertension were not independently significantly related to any of these outcomes. Pretreatment cardiologic consultation did not improve time on ibrutinib therapy, progression-free survival, overall survival, risk of stopping treatment due to cardiovascular side effects or risk of cardiovascular or sudden death, neither in the whole cohort nor in the subgroup of patients with and without pretreatment cardiac arrhythmia. Conclusions: Our analysis confirms the efficacy and tolerability of ibrutinib for the treatment of chronic lymphocytic leukemia. Patients older than 75 do significantly less well. Routine pretreatment cardiologic consultation does not improve outcomes and should not be considered part of standard pretreatment assessment without additional proof of its usefulness. Future investigations should aim at identifying predictive factors, mechanisms, and preventive strategies for reducing cardiotoxicity in chronic lymphocytic leukemia patients taking Bruton tyrosine kinase inhibitors.

Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks.

Background: Most Hodgkin lymphoma (HL) patients younger than 60 years are nowadays cured, especially those treated with front-line escalated BEACOPP (escBEACOPP), thus understanding long-term side effects is essential. Avascular joint necrosis (AVN) is a known side-effect of this regimen, possibly related to bone mineral density (BMD) loss. In order to reduce steroid-related side-effects, we reduced steroid exposure from the original 14 days to 7-8 days per escBEACOPP cycle without loss of efficacy and a trend towards reduced osteoarticular side effects. This study was performed to further investigate the impact of escBEACOPP and different steroid schedules on bone metabolism in patients with classical HL. Methods: Previously untreated patients with classical HL receiving at least two cycles of escBEACOPP for early unfavorable (EU, stage I - II with at least one unfavorable prognostic factor as per GHSG criteria) or advanced stage disease (AS, stage IIB bulky - IV), and at least one evaluable PET-CT for BMD assessment were included. BMD was assessed using the Hounsfield unit (HU) scale on axial images of the L3 vertebra from PET-CT scans performed at baseline, post-treatment, or during follow-up when available. The threshold for normal BMD was set at 160 HU, with values between 100-159 HU considered osteopenia and below 100 HU as osteoporosis. BMD reduction of ≥15% and ≥25% from baseline to post-treatment were considered clinically relevant. Demographic, treatment, steroid administration, and side-effects data were obtained retrospectively from patient medical records. Data were analyzed using descriptive statistics, chi-square tests, Fisher's exact tests, repeated measures ANOVA, t-tests, and logistic regression analysis. Results: The study cohort consisted of 177 patients (56.5% male, median age 31 years, all Caucasian). Seventy-four % had AS disease, of which 61% were stage IV. Sixty-two % received 6 cycles of escBEACOPP, 22% received 2 cycles of escBEACOPP + 2 cycles of ABVD, and 16% other combinations. BMD changed significantly across all time points (p<0.001). Baseline mean BMD was 204.71 (SD = 44.4), decreasing to 161.49 (SD = 43.84) post-treatment and 170.77 (SD = 49.45) at follow-up. Baseline BMD measurements showed normal BMD in 84.8% of patients, 13.6% had osteopenia, and 1.7% had osteoporosis. Post-treatment, the proportions were 50.6% normal, 42.9% osteopenia, and 6.5% osteoporosis. The median BMD reduction from baseline to post-treatment for 117 evaluable patients was 23%, with 64% of patients having a BMD reduction ≥15% and 45% ≥25%. During follow-up, the median BMD reduction from baseline for 44 evaluable patients was 18%, with 54% of patients having a reduction ≥15% and 22% ≥25%. Age (stratified by groups <30, 31-40, 41-50, 50+y) significantly influenced the risk of having osteopenia at baseline (OR 4.79, p<0.001). Age was also significantly associated with the risk of developing osteoporosis after treatment (p<0.001, OR 5.85). Stage IV disease was a significant predictor of BMD reduction of ≥15% (p = 0.01), whereas age, gender, baseline BMD, EU vs. AS, and number of BEACOPP cycles were not. Only age presented an increased risk of a more significant BMD decline by ≥25% (p=0.014, OR 1.85). The decrease in steroid dosing from 14 to 7-8 days of prednisone per cycle did not significantly impact BMD outcomes (p=0.404 for reduction≥15%; p=0.51 for ≥25%). There was no correlation between BMD dynamics and the development of clinically relevant osteoarticular events (13 pts, 7.23%). No pathological fractures were documented. Conclusions: This study highlights a significant reduction in BMD in HL patients treated with escBEACOPP, with only minor recovery during follow-up. Despite efforts to reduce steroid-related bone loss by decreasing steroid exposure, no significant improvements were observed. The BMD reduction was more pronounced in older patients and in patients with stage IV disease, regardless of number of escBEACOPP cycles, suggesting that certain host and disease characteristics likely contribute to BMD loss in addition to therapy. Using routine PET-CT scans for BMD measurement in HU is feasible and easy to implement in everyday clinical practice. Abnormal results should trigger further work-up and DEXA confirmation. Long-term monitoring and intervention strategies, as well as development of less toxic regimens, are crucial for managing bone health in HL patients.