Paradigm Shifts in Hodgkin Lymphoma Treatment: From Frontline Therapies to Relapsed Disease.

Combination chemotherapy with or without radiation has served as the primary therapeutic option for classic Hodgkin lymphoma (cHL), leading to durable remission in a majority of patients with early- and advanced-stage cHL. Patients with relapsed/refractory (RR) cHL could still be cured with salvage chemotherapy and autologous stem-cell transplantation. Brentuximab vedotin (BV) and the anti-PD-1-blocking antibodies, nivolumab and pembrolizumab, are highly effective treatments for cHL and have revolutionized the management of the disease. Recent studies incorporating BV and PD-1 blockade into salvage therapy for RR cHL and into frontline treatment regimens have changed the cHL treatment paradigm. The novel agents are also useful in the treatment of older patients who have poor outcomes with traditional therapy. This manuscript will review current strategies for approaching the management of previously untreated, RR, and challenging populations with cHL, including how to incorporate the novel agents.

Distinct autoantibody profiles across checkpoint inhibitor types and toxicities.

Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

Future perspectives of radiation therapy for Hodgkin Lymphoma: Risk-adapted, response-adapted, and safer than before.

Classical Hodgkin lymphoma is a lymphoproliferative disease with a good prognosis mainly seen in young people. Nevertheless secondary malignancy, cardiac disease and infertility may affect the long survivors with significant impact on quality of life, morbidity and overall survival. In the last decades several treatment strategies were evaluated to reduce the toxicity of first line treatment such as avoiding radiotherapy or its reduction in terms of dosage and extension. Many trials including interim Positron Emission Tomography evaluation fail to compare efficacy between combined modality treatment versus chemotherapy alone in particular in early stage disease. In this review we analyze which subset of patients could take advantage from proton therapy in terms of toxicity and cost effectiveness.

Efficacy and Nuances of Precision Molecular Engineering for Hodgkin's Disease to a Gene Therapeutic Approach.

Gene therapy is a particularly useful treatment for nervous system genetic diseases, including those induced especially by infectious organisms and antigens, and is being utilized to treat Hodgkin's disease (HD). Due to the possible clonal relationship between both disorders, immunotherapy directed against CD20 positive cells may be a more effective treatment in patients with persistent HD and NHL. HL growth can be inhibited both in vitro and in vivo by AdsIL-13Ralpha2. High-dose treatment combined with stem cell transplantation has been effective in treating HIV-negative lymphoma that has progressed to high-risk or relapsed disease. For therapy, LMP2-specific CTL will be used. Furthermore, it is possible to view the cytotoxicity of genetically modified adenoviruses that express proteins such as p27Kip1, p21Waf1, and p16INK4A as a foundational element for (2,5)-derived ALCL genetic treatment for Hodgkin's disease.

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

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

[A Real-World Single-Center Study of Adult Hodgkin's Lymphoma].

OBJECTIVE: To summarize the clinical characteristics, therapeutic effect and prognostic factors of patients with Hodgkin's lymphoma (HL). METHODS: A total of 129 patients with HL diagnosed in Peking University Third Hospital from January 2010 to March 2021 who were given at least one efficacy assessment after treatment were enrolled, and their clinical data, including sex, age, pathological type, Ann Arbor stage, ECOG score, blood test, ß2-microglobulin, lactate dehydrogenase level, albumin level were collected. The clinical characteristics, therapeutic effect and long-term prognosis of the patients were summarized and analyzed. RESULTS: In classical HL, nodular sclerosis HL accounted for the highest proportion of 51.6%, followed by mixed cellularity HL (36.5%), lymphocyte-rich classical HL (3.2%), and lymphocyte depletion HL (0.7%), while nodular lymphocyte predominant HL accounted for 4.8%. The 3-year overall survival (OS) rate of HL patients was 89.8%, and 5-year OS was 85.0%. The 3-year progression-free survival (PFS) rate was 73.4%, and 5-year PFS was 63.1%. Multivariate regression analysis indicated that IPI score was an independent negative factor, while hemoglobin (Hb) level was an independent positive factor for OS in HL patients. When the mediastinal mass size was 9.2 cm, it was most significant to judge the survival status of HL patients. 5-year OS and 5-year PFS were 97.4% and 76.0% in early-stage HL patients without large mass, respectively, while in patients with advanced-stage HL was 83.4% and 55.9% (both P < 0.05). After 2-4 courses of treatment, the overall response rate (ORR) of patients who received chemotherapy combined with radiotherapy was 95.0%, while that was 89.6% in those with chemotherapy alone. CONCLUSIONS: The overall prognosis of patients with HL is satisfactory, especially those in early-stage without large mass. IPI score and Hb level are independent risk factors for the prognosis of HL patients. A 9.2 cm mediastinal mass can be used as the cut-off value for the prognosis of Chinese HL patients.

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

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

Real-life study on the use of response adapted therapy in patients with Hodgkin Lymphoma: Results from a multicenter experience.

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes.

Anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation in patients with high-risk CD30+ lymphoma: a phase 1 study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.

Vogt-Koyanagi-Harada disease developed during chemotherapy for Hodgkin lymphoma: a case report.

BACKGROUND: Ocular manifestations are known for non-Hodgkin lymphoma, but are rare for Hodgkin lymphoma. We report a case of Vogt-Koyanagi-Harada (VKH) disease presenting as serous retinal detachment and uveitis in both eyes in a child undergoing chemotherapy for Hodgkin lymphoma. CASE PRESENTATION: The patient was a 7-year-old boy with stage IIB Hodgkin lymphoma (nodular lymphocyte predominant type) who was undergoing chemotherapy, including 2 cycles of the OEPA regimen and 1 cycle of the COPDAC regimen. Two days after the end of the COPDAC regimen, the patient complained of headache and of blurred and decreased vision in both eyes. On the basis of optic symptoms, such as uveitis and serous retinal detachment in both eyes, increased cell counts in cerebrospinal fluid, and positivity for human leukocyte antigen (HLA)-DR4 in peripheral blood cells, incomplete VKH disease was diagnosed. Intravenous treatment with high-dose prednisolone (60mg/m2/day) for 7 days improved both visual acuity and serous retinal detachment and enabled the remains of the COPDAC chemotherapy cycle to be administered. With prednisolone treatment, visual acuity improved from 20/500 to 20/20 in the right eye and from 20/63 to 20/25 in the left eye. Because multiple vitiligo lesions later appeared in the abdomen, complete VKH disease was finally diagnosed. CONCLUSION: The onset of VKH disease occurred during chemotherapy for Hodgkin lymphoma. The patient was HLA-DR4-positive and might have had a predisposition to develop autoimmune diseases, including VKH disease. However, the anticancer drugs administered to this patient have not been reported to cause uveitis. Whether Hodgkin lymphoma triggered the development of VKH remains unclear. Early diagnosis of VKH disease and prompt treatment with high-dose prednisone enabled the patient to maintain good visual function despite chemotherapy for Hodgkin lymphoma.

Epstein-Barr virus latency patterns in polymorphic lymphoproliferative disorders and lymphomas in immunodeficiency settings: Diagnostic implications.

Epstein-Barr virus (EBV) is responsible for many B cell lymphoproliferative disorders (LPD) spanning subclinical infection to immunodeficiency-related neoplasms. EBV establishes a latent infection in the host B cell as defined histologically by the expression of EBV latent membrane proteins and nuclear antigens. Herein, we characterize the latency patterns of immunodeficiency-related neoplasms including post-transplant lymphoproliferative disorders (PTLD) and therapy-related LPD (formerly iatrogenic) with latent membrane protein-1 (LMP-1) and EBV nuclear antigen-2 (EBNA-2) immunohistochemistry. The latency pattern was correlated with immunodeficiency and dysregulation (IDD) status and time from transplant procedure. 38 cases of EBV+ PTLD in comparison to 27 cases of classic Hodgkin lymphoma (CHL) and diffuse large B cell lymphoma (DLBCL) arising in either the therapy-related immunodeficiency setting (n = 12) or without an identified immunodeficiency (n = 15) were evaluated for EBV-encoded small RNAs by in situ hybridization (EBER-ISH) and for LMP-1 and EBNA-2 by immunohistochemistry. A full spectrum of EBV latency patterns was observed across PTLD in contrast to CHL and DLBCL arising in the therapy-related immunodeficiency setting. Polymorphic-PTLD (12 of 16 cases, 75 %) and DLBCL-PTLD (9 of 11 cases, 82 %) showed the greatest proportion of cases with latency III pattern. Whereas, EBV+ CHL in an immunocompetent patient showed exclusively latency II pattern (13 of 13 cases, 100 %). The majority of EBV+ PTLD occurred by three years of transplant procedure date and were enriched for latency III pattern (21 of 22 cases, 95 %). Immunohistochemical identification of EBV latency by LMP-1 and EBNA-2 can help classify PTLD in comparison to other EBV+ B cell LPD and lymphomas arising in therapy-related immunodeficiency and non-immunodeficiency settings.

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

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

Evidence for external beam radiotherapy in mediastinal Hodgkin and non-Hodgkin lymphoma - systematic review.

INTRODUCTION AND OBJECTIVE: Proton beam therapy (PBT) provides the opportunity for a more localized delivery of high energy protons and may reduce the damage to healthy tissues and vital organs. The aim of this review was to assess the effects of proton therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma treated with mediastinal irradiation. REVIEW METHODS: A systematic search of EMBASE, MEDLINE via OVID and Cochrane Library was conducted in May 2022 according to PRISMA guidelines to identify relevant data on the efficacy and toxicity of proton beam therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: Of 566 screened abstracts (430 after de-duplication) 11 studies with a total of 529 patients were included. All studies were case series published between 2011-2021. Median range of follow-up time was 15-63.6 months. The overall survival (OS) for 2 years varied from 91% - 98% for 5 of the included studies. Three of the included studies had favourable outcomes with 2-year progression-free survival (PFS) ranging from 73% - 94%. Skin reaction, oesophagitis and fatigue were found to be the most common grade 1 and grade 2 toxicities. No acute or late grade 4 and higher toxicities/adverse events were observed. SUMMARY: There are data indicating that PBT may to be an effective treatment against mediastinal Hodgkin and non-Hodgkin lymphoma. Because all the studies were case series, the authors of this review have little confidence in the evidence. There remains a need for well-designed randomized controlled trials to inform about the optimal approach to proton irradiation in HL and NHL.

Genetically determined telomere length as a risk factor for hematological malignancies: evidence from Mendelian randomization analysis.

BACKGROUND: Over the past years, the exact correlation between telomere length and hematological malignancies was still not fully understood. METHODS: We performed a two-sample Mendelian randomization study to investigate the causal relationship between telomere length and hematological malignancies. We selected genetic instruments associated with telomere length. The genetic associations for lymphoid and hematopoietic malignant neoplasms were obtained from the most recent publicly accessible FinnGen study R9 data. Inverse variant weighted (IVW) analysis was adopted as the primary method, and we also performed the weighted-median method and the MR-Egger, and MRPRESSO methods as sensitive analysis. RESULTS: Significant associations have been observed between telomere length and primary lymphoid (IVW: OR = 1.52, P = 2.11 × 10-6), Hodgkin lymphoma (IVW: OR = 1.64, P = 0.014), non-Hodgkin lymphoma (IVW: OR = 1.70, P = 0.002), B-cell lymphoma (IVW: OR = 1.57, P = 0.015), non-follicular lymphoma (IVW: OR = 1.58, P = 1.7 × 10-3), mantle cell lymphoma (IVW: OR = 3.13, P = 0.003), lymphoid leukemia (IVW: OR = 2.56, P = 5.92E-09), acute lymphocytic leukemia (IVW: OR = 2.65, P = 0.021) and chronic lymphocytic leukemia (IVW: OR = 2.80, P = 8.21 × 10-6), along with multiple myeloma (IVW: OR = 1.85, P = 0.016). CONCLUSION: This MR study found a significant association between telomere length and a wide range of hematopoietic malignancies. But no substantial impact of lymphoma and hematopoietic malignancies on telomere length has been detected.

Texture analysis of 18F-FDG PET/CT and CECT: Prediction of refractoriness of Hodgkin lymphoma with mediastinal bulk involvement.

To recognize patients at high risk of refractory disease, the identification of novel prognostic parameters improving stratification of newly diagnosed Hodgkin Lymphoma (HL) is still needed. This study investigates the potential value of metabolic and texture features, extracted from baseline 18F-FDG Positron Emission Tomography/Computed Tomography (PET) and Contrast-Enhanced Computed Tomography scan (CECT), together with clinical data, in predicting first-line therapy refractoriness (R) of classical HL (cHL) with mediastinal bulk involvement. We reviewed 69 cHL patients who underwent staging PET and CECT. Lesion segmentation and texture parameter extraction were performed using the freeware software LIFEx 6.3. The prognostic significance of clinical and imaging features was evaluated in relation to the development of refractory disease. Receiver operating characteristic curve, Cox proportional hazard regression and Kaplan-Meier analyses were performed to examine the potential independent predictors and to evaluate their prognostic value. Among clinical characteristics, only stage according to the German Hodgkin Group (GHSG) classification system significantly differed between R and not-R. Among CECT variables, only parameters derived from second order matrices (gray-level co-occurrence matrix (GLCM) and gray-level run length matrix (GLRLM) demonstrated significant prognostic power. Among PET variables, SUVmean, several variables derived from first (histograms, shape), and second order analyses (GLCM, GLRLM, NGLDM) exhibited significant predictive power. Such variables obtained accuracies greater than 70% at receiver operating characteristic analysis and their PFS curves resulted statistically significant in predicting refractoriness. At multivariate analysis, only HISTO_EntropyPET extracted from PET (HISTO_EntropyPET ) and GHSG stage resulted as significant independent predictors. Their combination identified 4 patient groups with significantly different PFS curves, with worst prognosis in patients with higher HISTO_EntropyPET values, regardless of the stage. Imaging radiomics may provide a reference for prognostic evaluation of patients with mediastinal bulky cHL. The best prognostic value in the prediction of R versus not-R disease was reached by combining HISTO_EntropyPET with GHSG stage.

Remission of relapsed/refractory classical Hodgkin lymphoma induced by brentuximab vedotin and pembrolizumab combination after allogeneic hematopoietic stem cell transplantation: a case report.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with highly chemorefractory Hodgkin lymphoma (HL). The CD30-targeting antibody-drug conjugate Brentuximab-Vedotin (BV) and programmed cell death protein-1 (PD-1) blocking agents have demonstrated clinical activity with durable responses in relapsed/refractory (r/r) HL. However, patients with a history of allo-HSCT were frequently excluded from clinical trials due to concerns about the risk of graft-versus-host disease (GVHD). We report the clinical history of a patient with refractory classical HL who underwent two allo-HSCTs (first from matched unrelated and second from haploidentical donor) after relapsing on BV and nivolumab and for whom durable remission was finally obtained using BV-pembrolizumab combination for relapse after haploidentical HSCT. Such treatment was associated with the onset of GVHD after only two cycles which led to treatment discontinuation. However, the side effects were rapidly controlled, and after 2 years of follow-up, the patient is still in remission. Our data support the feasibility and efficacy of combining PD-1 blockade with BV to enhance the graft-versus-lymphoma effect after allo-HSCT.