ABSTRACT:The Lugano Imaging Committee recently refined the Deauville score (DS), subdividing DS5 into DS5a (>2× liver uptake without new lesions) and DS5b (new lesions). We investigated whether this improves prognostic discrimination at interim positron emission tomography (PET) after 2 cycles (PET-2) in patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) treated in recent German Hodgkin Study Group randomized phase 3 trials. The primary analysis cohort was HD18 postamendment standard arms (uniform treatment with 6 cycles of escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [eBEACOPP]); sensitivity cohorts were HD18 intention-to-treat and HD21 eBEACOPP and brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone arms. Progression-free survival (PFS) was analyzed by landmark Cox models starting at PET-2. DS5a was infrequent (4%-6% across cohorts; 39/639, 67/1745, 33/568, and 29/560). In the primary cohort, DS5 was associated with inferior PFS vs DS1 to DS3 (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.25-7.23) and vs DS1 to DS4 (HR, 2.35; 95% CI, 1.01-5.50). Across sensitivity cohorts, DS5a remained adverse compared with DS1 to DS4 (HR range, 2.57-5.47), whereas DS4 according to the new definition did not consistently separate from DS1 to DS3, which is likely a result of PET-adapted treatment. Overall survival trends were concordant, but interpretation is limited by few events. To our knowledge, this is the first prognostic validation of the refined DS in prospectively randomized trial populations. The newly introduced DS5a isolates a small high-risk AS-cHL, which further supports risk assessment and adaptation using quantitative biomarkers from PET. The HD18 and HD21 trials were registered at www.clinicaltrials.gov as NCT00515554 and NCT02661503, respectively.

BACKGROUND/PURPOSE:Proton therapy (PT) improves treatment precision for classical Hodgkin lymphoma (cHL), with computed tomography (CT) being essential for treatment planning and verification. This study evaluates the individual organ doses from CT imaging in these patients treated with PT using free-breathing (FB) or deep inspirational breath hold (DIBH) techniques. MATERIAL/METHODS:A cohort of 38 patients treated at the Skandion Clinic was studied. Organ doses from each planning and verification scan were estimated using VirtualDose software, based on CT parameters extracted from DICOM data. The impact of different imaging protocols (standard dose [SD], low dose [LD], and 4DCT) was assessed for patients with target in mediastinum, and neck and upper thorax. RESULTS:Significant variations were observed in the number of CT scans (median 9, range 3-12) and the protocols used among patients. Organ doses were further influenced by the extent of the scanning volume and the scanning technique. SD protocols in the mediastinum set resulted in median dose per scan to the lungs around 21 mGy (males and females), while LD protocol reduced these doses by up to 87%. The most exposed organs can receive a total dose of several hundred mGy. CONCLUSION:Large inter-patient variations highlight the need for personalized CT dose calculations. Although in-field and near-field organs may receive relatively high doses from imaging, these remain significantly lower than the prescribed dose, less than 2%. Nevertheless, organ doses and their associated risks for long-term survivors of cHL could be further minimized by implementing low-dose CT protocols whenever feasible.

PURPOSE:To propose a methodology for integrating the out-of-field and imaging doses to the in-field dose received by radiotherapy (RT) patients. In addition, the impact of considering the total dose in planning and radiation-induced second malignancies (RISM) risk assessment will be evaluated in several scenarios comprising photon and proton treatments. METHODS:The total dose is the voxel-wise sum of the doses from the different radiation sources (accounting for the radiobiological effectiveness) produced during the whole RT chain. The dose from the plan and imaging procedures were obtained by measurements for a photon prostate treatment and by calculation (combining treatment planning system, analytical models, and Monte Carlo simulations) for two lymphoma treatments, one using photons and the other, protons. Dose distributions, dose volume histograms (DVHs) metrics, mean organ doses, and RISM risks were evaluated for each radiation exposure in each treatment. RESULTS:In general, the contribution of the imaging doses is low compared to the dose administered during RT treatment, being higher in proton therapy. However, for some organs, for instance testes in the prostate case, the imaging dose becomes higher than the scattered dose from the treatment fields. Plan evaluations revealed shifts in cumulative DVHs with the inclusion of out-of-field and imaging doses, though minimal clinical impact is expected. Risk assessment showed increased estimates with total dose. CONCLUSIONS:The methodology enables accounting for the total dose for optimization of plans and imaging protocols, prospective risk predictions and retrospective epidemiological analyses.

Older patients with classical Hodgkin lymphoma (cHL) have lower tolerance and inferior outcomes after standard chemotherapy regimens. To identify patient-derived indicators of frailty associated with outcome, we retrospectively analyzed patient and disease characteristics, treatment and outcome in a Norwegian population-based cohort of older (≥60 years) patients with cHL diagnosed 2000-2015. We included 279 patients (median age 69 years, range 60-90) treated with curative intent, defined as any typical cHL regimen with ≥50% standard doxorubicin dose in the first cycle. In this Norwegian cohort, treatment-related mortality was 8%, median progression-free survival (PFS) and overall survival (OS) were 7.1 years (95% confidence interval [CI]: 5.0-9.3) and 8.7 years (95% CI: 7.0-10.4), respectively. Multivariable analyses identified patient-derived prognostic factors working independently of stage, histology, and International Prognostic Score. We derived a frailty index ranging from 0-3 with one point each for age ≥70 years, Eastern Cooperative Oncology Group status ≥2, and a Cumulative Illness Rating Scale in Geriatrics score ≥8. Patients were categorized as fit (score 0, 34% of patients), unfit (score 1-2, 60%), and frail (score 3, 7%), with 5-year PFS of 74%, 49%, and 11%, and 5-year OS of 86%, 52%, and 22%, respectively. The proposed frailty score was validated in an external cohort of 792 similarly selected patients from the Swedish Lymphoma Register, where comorbidities were scored based on the Charlson comorbidity index (0-2 vs. 3 or higher). In this comprehensive study, we develop a frailty score for elderly cHL patients to inform clinical decisions and prospective trials evaluating selective therapies for older patients.

Childbirth rates in classical Hodgkin lymphoma (cHL) survivors have historically been reduced compared to the general population. Understanding if contemporary treatment protocols are associated with reduced fertility is crucial as treatment guidelines shift toward more liberal use of intensive chemotherapy. We identified 2834 individuals aged 18‐40 years with cHL in Swedish and Danish lymphoma registers, and in the clinical database at Oslo University Hospital diagnosed 1995‐2018, who were linked to national medical birth registers. Cox regression adjusted for stage, performance status, year, and age at diagnosis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) contrasting time to first childbirth by treatment groups (ABVD, 2‐4 BEACOPP, 6‐8 BEACOPP) up to 10 years after diagnosis. Overall, 74.8% of patients were treated with ABVD, 3.1% with 2‐4 BEACOPP and 11.2% with 6‐8 BEACOPP. Adjusted HRs comparing childbirth rates in individuals treated with 6‐8 BEACOPP, and 2‐4 BEACOPP to ABVD were 0.53 (CI: 0.36‐0.77) and 0.33 (CI: 0.12‐0.91) for males, and 0.91 (CI: 0.61‐1.34) and 0.38 (CI: 0.12‐1.21) for females. Cumulative incidence of childbirths after 10 years was 19.8% (CI: 14.5%‐27.0%) for males and 34.3% (CI: 25.8%‐45.6%) for females treated with 6‐8 BEACOPP. Proportions of children born after assisted reproductive technique (ART) treatments were 77.4% (CI: 60.2‐88.6%) for males following 6‐8 BEACOPP, and <11% for females. Among ABVD treated patients the corresponding proportions were 12.2% (CI: 8.5%‐17.3%) and 10.6% (CI: 7.4%‐14.9%). BEACOPP treatment is associated with decreased childbirth rates compared to ABVD in male, but not female, cHL patients, despite widespread access to ART in the Nordics.

In this issue of Blood, Eichenauer et al(1) concludes that contemporary Hodgkin lymphoma-directed treatment is highly active in newly diagnosed early-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Their important findings originate from subgroup analyses of 2 randomized Hodgkin lymphoma trials. Owing to the scarcity of NLPHL, large randomized trials are absent. Thus, evidence for treatment decisions is hard to find.

BACKGROUND:Hodgkin lymphoma (HL) treatment protocols for children, adolescents and young adults traditionally differ, but the biological and clinical justification for this remains uncertain. MATERIAL AND METHODS:We compared age-dependent clinical presentation and treatment and outcome for 1072 classical HL patients 0-24 years diagnosed in Denmark (1990-2010) and Sweden (1992-2009) in pediatric (n = 315, Denmark <15 years, Sweden <18 years) or adult departments (n = 757). Distribution of clinical characteristics was assessed with Pearson's chi2-test and Mantel-Haenszel trend test. The Kaplan-Meier method was used for survival analyses. Hazard ratios (HR) were used to compare the different treatment groups and calculated using Cox regression. RESULTS:Children (0-9 years) less often presented with advanced disease than adolescents (10-17 years) and young adults (18-24 years) (stage IIB-IV: children 32% vs. adolescents 50%, and adults 55%; p < .005). No variation in overall survival (OS) was seen between pediatric and adult departments or by country. Danish pediatric patients received radiotherapy (36%) less frequently than Swedish pediatric patients (71%) (p < .0001). Ten-year event-free survival (EFS) was lower among Danish pediatric patients (0-14 years) (0.79; 95% confidence interval (CI) 0.70-0.86) than among Swedish pediatric patients (0-17 years) (0.88; 95% CI 0.83-0.92), HR (1.93; 95% CI 1.08-3.46). A similar pattern was seen between adult patients in the two countries: Denmark 10-year EFS 0.85 (95% CI 0.81-0.88), Sweden 0.88 (95% CI 0.84-0.91), adjusted HR 1.51 (95% CI 1.03-2.22). CONCLUSION:Adolescents and young adults shared similar clinical presentation suggesting a rationale of harmonized treatment for these groups. Both adult and pediatric protocols provided high OS with no significant difference between the departments. The less frequent use of radiotherapy in Danish pediatric patients corresponded to a lower EFS, but comparable OS in all groups confirmed effective rescue strategies for the relapsing patients.