Refractory Hodgkin Lymphoma Research Articles

Outcomes for Patients with Classical Hodgkin Lymphoma Who Relapse after Autologous Stem Cell Transplant in the Era of Novel Therapies

Background: For patients with relapsed and refractory (R/R) classical Hodgkin lymphoma (HL), the standard of care remains salvage therapy followed by autologous stem cell transplant (ASCT) for responding patients. Historical data suggest 40% of patients may relapse after ASCT, and these patients have generally a poor median overall survival (OS) of less than 2 years (Moskowitz et al., Br J Haematol. 2009;146(2):158-62). However, since these reports, the treatment landscape of R/R HL has dramatically improved, most notably with the introduction of two novel therapies, brentuximab vedotin (BV) and anti-PD1 agents. To refine our understanding of clinical outcomes in this context, we characterized patients who relapsed after ASCT in the modern era. Methods: We used a multicenter retrospective patient database at 5 transplant centers in the United States to identify patients with HL aged ≥ 12 years at diagnosis who had received ASCT on or after 1/1/2010. The primary objective was to determine the median OS for patients who relapsed after ASCT (post-ASCT-relapse OS), defining survival as the time from relapse after ASCT to subsequent death from any cause. Univariable Cox regression was performed to evaluate the impact of various factors on post-ASCT OS. Outcomes by era were evaluated using three different eras based on approval dates of novel agents: (1) pre-BV approval (pre-7/31/2011), (2) post-BV approval (8/1/2011-4/30/2016), (3) post-anti-PD1 approval (5/1/16-present). Results: A total of 215 patients were identified. The median age at ASCT was 34. Before ASCT, 128 patients (62%) had no exposure to novel agents, 76 patients (35%) had received BV and no anti-PD-1 therapy, and 11 patients (5.1%) had received anti-PD-1 therapy with or without BV. Conditioning was mostly with BEAM (59%) or CBV (32%). The median time to relapse after ASCT was 6 months (range: 1-109 months). Nearly half all relapses (47%) occurred within 6 months of ASCT. Only 14% of relapses occurred after 1 year. Among 126 patients with available treatment information, the median number of post-ASCT lines of therapy was 2 (IQR: 1, 4). Therapy for post-ASCT relapse included BV and no anti-PD-1 therapy in 41 patients (29%), anti-PD-1 therapy with or without BV for 70 patients (50%), and no novel agents for only 15 patients (11%). The median followup time from the date of ASCT among survivors was 5.0 (IQR: 2.8, 7.8) years. The median post-ASCT-relapse OS was not reached ( Figure 1). The 2- and 5-year post-ASCT-relapse OS were 75% (95% CI: 70%-81%) and 59% (95% CI: 53%-67%), respectively. On univariable Cox regression for post-ASCT-relapse OS ( Table 1), time to relapse greater than 6 (HR 0.55, 95% CI 0.35-0.85) or 12 months (HR 0.53, 95% CI 0.29-0.96) were significantly associated with improved post-ASCT-relapse OS. Increasing age at relapse was associated with worse OS (HR 1.05, 95% CI 1.04-1.07). Receipt of a novel agent (compared to chemotherapy alone) as the first salvage regimen for post-ASCT relapse was associated with improved post-ASCT OS (BV: HR 0.43, 95% CI 0.20-0.96; anti-PD-1: HR 0.44, 95% CI 0.18-1.08). Outcomes improved over time as regulatory approvals for novel agents occurred (post-BV-approval: HR 0.70, 95% CI 0.39-1.24; post-anti-PD-1 approval: HR 0.45, 95% CI 0.23-0.91). Conclusion: We show prolonged overall survival post-ASCT relapse compared to historical data likely due to the introduction of BV and anti-PD1 agents. This report represents one of the largest datasets of post-ASCT relapse in cHL, and this data should serve as an updated benchmark for future evaluations.

Clinical experience of using brentuximab-vedotin as therapy in relapsed/refractory Hodgkin's lymphoma at Hospital Guillermo Grant Benavente, Concepción, Chile

Hodgkin's lymphoma is a B-cell neoplasm with a good prognosis but a poor response to chemotherapy in refractory or relapsed cases. Brentuximab-vedotin is an anti-CD30 monoclonal antibody approved for use in these cases. This study aims to describe the clinical experience of patients treated with brentuximab-vedotin through expanded access modality. A retrospective study on clinical information of patients diagnosed with refractory or relapsed Hodgkin's lymphoma treated with brentuximab-vedotin at the Regional Hospital of Concepción in the period 2015-2021. 7 patients were identified, 5/7 male, with a median age of 35 years (21-50). Five cases were mixed cellularity, and two were nodular sclerosis. Four were in stage II, 1/7 in stage III, and 3/7 in stage IV. The median number of previous treatment lines was 4 (3-5), and the relapse was post-transplantation in two cases. In 6/7 cases, brentuximab-vedotin was used as induction, and in one case, it was used as post-autologous bone marrow transplant maintenance. The administration was outpatient via a peripheral route with a median dose of 150 mg and ten cycles. In one case, dose adjustment was required due to toxicity. Three out of 6 patients achieved complete remission and underwent autologous stem cell transplantation. brentuximab-vedotin is an outpatient medication with low toxicity that can optimize the treatment of patients with relapsed-refractory Hodgkin's lymphoma.

The Role of Radiotherapy in Patients with Refractory Hodgkin Lymphoma after Brentuximab Vedotin and -/or Immune Checkpoint Inhibitors

Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) had important roles in the treatment of relapse or refractory (R/R) Hodgkin lymphoma (HL). Treatment of refractory disease after BV and -/or ICIs remains a challenge. This study was conducted to evaluate the efficacy and safety of radiotherapy for R/R HL after failure to BV or ICIs. We retrospectively analyzed patients in two institutions with R/R HL who had failed after first-line therapy, and were refractory to BV or ICIs, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 19 patients were enrolled. First-line systemic therapy consisted of ABVD (84.2%), AVD + ICIs (10.5%) and BEACOPP (5.3%), respectively. After first-line therapy, 15 patients (78.9%) were refractory, and 4 patients (21.1%) relapsed. After diagnosis of R/R HL, 8 patients (42.1%) received BV, and 17 patients (89.5%) received ICIs. RT was delivered in all 19 patients who failed after BV or ICIs. In 16 efficacy-evaluable patients, the ORR and CR rate were 100% and 100%. The median DOR was 17.2 months (range, 7.9 to 46.7 months). 3 patients progressed at outside of the radiation field. The in-field-response rate was 100%. The 12-month PFS and OS were 84.4% and 100%, respectively. No patients were reported with sever adverse events. This study concluded that radiotherapy was effective and safe for refractory HL after BV or ICIs. Further prospective studies were warranted.

Consolidative Radio therapy in Place of Autologous Stem Cell Transplant in Patients with Low-Risk Relapsed/Refractory (R/R) Classic Hodgkin Lymphoma (cHL) Treated with Nivolumab plus Brentuximab Vedotin: CheckMate 744

Standard of care treatment for patients with relapsed and refractory classic Hodgkin lymphoma (RRHL) involves second line therapy followed by high dose therapy and autologous stem cell transplant (HDT/ASCT) and carries with it significant costs and toxicities to the patient. Some patients with RRHL may not require such intensive therapy, especially in the era of targeted chemotherapy and checkpoint inhibitors. CheckMate 744 (NCT02927769) evaluated a novel second-line therapy that omits HDT/ASCT by combining brentuximab vedotin (BV) and a nivolumab (N) followed by consolidative ISRT for low risk RRHL. Pts were aged 5-30 y and had one prior treatment without HDT/ASCT. Low-risk RRHL were those at relapse without B symptoms or extranodal disease, limited sites of relapse (≤4 sites of disease above the diaphragm or ≤3 sites above/below the diaphragm) AND with initial Stage IA, IIA with relapse <1 year if they received ≤3 cycles of chemotherapy and no RT OR Stage IA/B, IIA/B, IIIA ≥ 1 year. Patients received 4 cycles of N + BV induction. Patients with complete metabolic response (CMR) received an additional 2 cycles of N + BV before RT consolidation. Patients with suboptimal response received 2 cycles of BV + bendamustine intensification. Those patients achieving CMR proceeded to RT consolidation. RT was delivered to a dose of 30-30.6 Gy at 1.5-1.8 Gy/fraction to an ISRT volume. Among 28 pts treated, the median age (range) was 17 (6-27) years old and 64% of patients were aged < 18 y. Most (79%) pts had stage II disease at diagnosis and 82% had relapsed ≥ 12 months after first line treatment. Of 27 pts continuing in study after induction N + BV, 6 received bendamustine + BV intensification, and 92.9% achieved complete metabolic response. Twenty-two patients received RT consolidation. RT consolidation was delivered using 3D-CRT, IMRT, or proton therapy. After a median (range) follow-up of 31.8 (2.2-55.1) months, the 3-y event-free survival rate and progression-free survival were 86.9% (69.5-94.7%) and 95% (76.7-99%), respectively. A novel combination of N + BV followed by ISRT was an effective second line therapy. This treatment regimen allowed patients to forgo high dose therapy and transplant in favor of consolidative radiotherapy using ISRT. Larger studies challenging the role of high dose therapy and transplant are needed for RRHL.

Long-term survival benefit of anti-PD-1 therapy in patients with relapsed or refractory classical Hodgkin lymphoma

Anti-programmed cell death-1 (anti-PD-1) therapies have shown a favorable efficacy and good tolerance for relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). However, there are limited data on long-term outcomes among patients with r/r cHL who achieve an objective response to anti-PD-1 therapies. A total of 260 responders from four, phase 2 clinical trials were included in this study. The median age was 32 years with a male/female ratio of 1.3:1. After a median follow-up period of 31.1 months, 116 (44.6%) responders experienced disease progression and 18 (6.9%) died. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 55.1% and 89.7% overall. Patients with partial remission (PR) had inferior outcomes compared with those who achieved complete remission (3-year PFS, 29.5% vs. 72.3%, P < 0.001; 3-year OS, 81.5% vs. 94.4%, P = 0.017). Moreover, the survival outcome was inferior for patients with refractory disease compared with those with relapsed disease. Multivariate Cox regression analysis showed PR and refractory disease were independent risk factors for PFS. In conclusion, PR and refractory disease have a negative impact on the survival benefit of anti-PD-1 therapeutics in patients with r/r cHL, which highlights the need for multimodal treatment strategies.

Prognostic model using 18F-FDG PET radiomics predicts progression-free survival in relapsed/refractory Hodgkin lymphoma

AbstractInvestigating prognostic factors in patients with relapsed or primary refractory classical Hodgkin lymphoma (R/R cHL) is essential to optimize risk-adapted treatment strategies. We built a prognostic model using baseline quantitative 18F-fluorodeoxyglucose positron emission tomography (PET) radiomics features and clinical characteristics to predict the progression-free survival (PFS) among patients with R/R cHL treated with salvage chemotherapy followed by autologous stem cell transplantation. Metabolic tumor volume and several novel radiomics dissemination features, representing interlesional differences in distance, volume, and standard uptake value, were extracted from the baseline PET. Machine learning using backward selection and logistic regression were applied to develop and train the model on a total of 113 patients from 2 clinical trials. The model was validated on an independent external cohort of 69 patients. In addition, we validated 4 different PET segmentation methods to calculate radiomics features. We identified a subset of patients at high risk for progression with significant inferior 3-year PFS outcomes of 38.1% vs 88.4% for patients in the low-risk group in the training cohort (P < .001) and 38.5% vs 75.0% in the validation cohort (P = .015), respectively. The overall survival was also significantly better in the low-risk group (P = .022 and P < .001). We provide a formula to calculate a risk score for individual patients based on the model. In conclusion, we developed a prognostic model for PFS combining radiomics and clinical features in a large cohort of patients with R/R cHL. This model calculates a PET-based risk profile and can be applied to develop risk-stratified treatment strategies for patients with R/R cHL. These trials were registered at www.clinicaltrials.gov as #NCT02280993, #NCT00255723, and #NCT01508312.

Cost-effectiveness of brentuximab vedotin in Hodgkin lymphoma: a systematic review.

This study aimed to systematically review and critically appraise cost-effectiveness studies on Brentuximab vedotin (BV) in patients with Hodgkin lymphoma (HL). The PubMed, Scopus, Web of Science core collection, and Embase databases were searched until July 3, 2022. We included published full economic evaluation studies on BV for treating patients with HL. The methodological quality of the studies was assessed using the Quality of Health Economic Studies (QHES) checklist. Meanwhile, we used qualitative synthesis to analyze the findings. We converted the incremental cost-effectiveness ratios (ICERs) to the value of the US dollar in 2022. Eight economic evaluations met the study's inclusion criteria. The results of three studies that compared BV plus doxorubicin, vinblastine, and dacarbazine (BV + AVD) front-line therapy with doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) showed that BV is unlikely to be cost-effective as a front-line treatment in patients advanced stage (III or IV) HL. Four studies investigated the cost-effectiveness of BV in patients with relapsed or refractory (R/R) HL after autologous stem cell transplantation (ASCT). BV was not cost-effective in the reviewed studies at accepted thresholds. In addition, the adjusted ICERs ranged from $65,382 to $374,896 per quality-adjusted life-year (QALY). The key drivers of cost-effectiveness were medication costs, hazard ratio for BV, and utilities. Available economic evaluations show that using BV as front-line treatment or consolidation therapy is not cost-effective based on specific ICER thresholds for patients with HL or R/R HL. To decide on this orphan drug, we should consider other factors such as existence of alternative treatment options, clinical benefits, and disease burden.

HL-252 MCVAC Conditioning Regimen Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Relapsed and Refractory Hodgkin Lymphoma: A Single-Institution Retrospective Study

HL-252 MCVAC Conditioning Regimen Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Relapsed and Refractory Hodgkin Lymphoma: A Single-Institution Retrospective Study

POSTER: HL-252 MCVAC Conditioning Regimen Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Relapsed and Refractory Hodgkin Lymphoma: A Single-Institution Retrospective Study

POSTER: HL-252 MCVAC Conditioning Regimen Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Relapsed and Refractory Hodgkin Lymphoma: A Single-Institution Retrospective Study

Un érythème polymorphe bulleux mimant un syndrome de Sweet

We report a case of bullous polymorphous erythema mimicking Sweet syndrome in a 34-year-old patient treated for refractory classical sclerodular Hodgkin's lymphoma treated with chemotherapy 10 days before the onset of symptoms, in whom the diagnosis of Sweet syndrome was strongly suspected based on the presence of several diagnostic criteria, but skin biopsy was in favor of bullous polymorphous erythema.

Assessment of Effectiveness and Adverse Effect of New Combination Chemotherapy (irinotecan, cisplatin, and dexamethasone) in Relapse and Refractory Hodgkin Lymphoma.

Background: Chemotherapy with Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD regimen) cannot cure all patients with Hodgkin lymphoma. In this study, we evaluated the efficacy and adverse effect of a new regimen consist Irinotecan, Cisplatin, and Dexamethasone (ICD) in relapsed and refractory Hodgkin lymphoma as the second to fifth line of treatment. Materials and Methods: We performed a retrospective study in 26 relapsed or refractory patients with Hodgkin lymphoma receiving at least the first-line chemotherapy regimen (ABVD) and (ICD) as salvage therapy in Thaleghany Hospital from 2012 to 2018. This regimen consisted of Irinotecan 65mg/m2 D1, D8, Cisplatin 30mg/m2 D1, D8, and dexamethasone 40mg D1, 2, 8, and 9 was administered every 3 weeks for 6 cycles. Treatment was discontinued in cases of disease progression or severe toxicity. Response to treatment was evaluated after two cycles. Patients with complete and partial remission were candidates for high-dose chemotherapy and autologous stem cell transplantation. Twenty-four patients were enrolled in the study. The mean age of 22 patients was 31.5 (19-67) years. Seven patients (29.1%) were in the first recurrence, and 17 (70.8%) were in the second or subsequent recurrence. Results: According to this study, three patients (12.5%) had complete response, 13 (45%) had partial response, four (16.6%) had stable disease, and four (16.6%) had progressive disease. Nine patients (37.5%) received high-dose chemotherapy and autologous stem cell support after ICD regimen. None of the cycles of chemotherapy were delayed due to treatment-related adverse event. Overall survival after six months in all patients was 91%, and mortality rate was 8.3% at the end of the study. Conclusion: The goal of salvage chemotherapy in relapsed or refractory Hodgkin Lymphoma is achieving CR or PR preparation patients for stabilization with BMT. Thus, we recommend ICD as one of the most effective protocols with overall response rate of 66% in this population.

Nivolumab plus Brentuximab vedotin +/- bendamustine combination therapy: a safe and effective treatment in pediatric recurrent and refractory classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is the most common pediatric lymphoma. Approximately 10% of patients develop refractory or recurrent disease. These patients are treated with intensive chemotherapy followed by consolidation with radiotherapy or high-dose chemotherapy and autologous stem cell reinfusion. Although this treatment is effective, it comes at the cost of severe long-term adverse events, such as reduced fertility and an increased risk of secondary cancers. Recently, promising results of inducing remission with the immune checkpoint inhibitor nivolumab (targeting PD-1) and the anti-CD30 antibody-drug conjugate Brentuximab vedotin (BV) +/- bendamustine were published. Here we describe a cohort of 10 relapsed and refractory pediatric cHL patients treated with nivolumab + BV +/- bendamustine to induce remission prior to consolidation with standard treatment. All patients achieved complete remission prior to consolidation treatment and are in ongoing complete remission with a median follow-up of 25 months (range: 12 to 42 months) after end-of-treatment. Only one adverse event of CTCAE grade 3 or higher due to nivolumab + BV was identified. Based on these results we conclude that immunotherapy with nivolumab + BV +/- bendamustine is an effective and safe treatment to induce remission in pediatric R/R cHL patients prior to standard consolidation treatment. We propose to evaluate this treatment further to study putative long-term toxicity and the possibility to reduce the intensity of consolidation treatment.

BET inhibitors induce NF-κB and E2F downregulation in Hodgkin and Reed–Sternberg cells

The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed–Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.

Brentuximab vedotin after autologous transplantation in pediatric patients with relapsed/refractory Hodgkin lymphoma.

Outcomes for children and adolescents with relapsed and refractory Hodgkin lymphoma (HL) are poor, with ∼50% of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate brentuximab vedotin improved progression-free survival (PFS) when used as consolidation after autologous stem cell transplantation (ASCT) in adults with high-risk relapsed/refractory HL. Data on brentuximab vedotin as consolidative therapy after ASCT in pediatric patients with HL are extremely limited, with data of only 11 patients reported in the literature. We performed a retrospective analysis of 67 pediatric patients who received brentuximab vedotin as consolidation therapy after ASCT for the treatment of relapsed/refractory HL to describe the experience of this regimen in the pediatric population. This is the largest cohort reported to date. We found that brentuximab vedotin was well tolerated with a safety profile similar to that of adult patients. With a median follow-up of 37months, the 3-year PFS was 85%. These data suggest a potential role for the use of brentuximab vedotin as consolidation therapy after ASCT for children with relapsed/refractory HL.

Outcome and toxicity of ifosfamide, carboplatin, and etoposide versus gemcitabine and vinorelbine regimen for pediatric patients with relapsed or refractory Hodgkin's lymphoma.

Pediatric classical Hodgkin lymphoma (CHL) is a curable disease; however, the optimal salvage regimen is unclear for relapsed/refractory (R/R) disease. This study aimed to compare response rates, toxicity, event-free survival (EFS), and overall survival (OS) of ifosfamide, carboplatin, and etoposide (ICE) with gemcitabine and vinorelbine (GV) regimen after first-line doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in pediatric patients with R/R CHL. This is a retrospective cohort study of 132 pediatric patients with R/R CHL treated from July 2012 to December 2020 with ICE (n = 82) or GV (n = 50). The median age at relapse was 13.9 years, and 68.2% were men. Rates of complete response, partial response, and progressive disease before consolidation were 50.6%, 3.7%, and 45.7% for ICE and 28.5%, 0%, and 71.5% for GV (P = 0.011). By multivariate analysis, regimen (P = 0.002), time to relapse (P = 0.0001), and B-symptoms (P = 0.002) were independent factors to lower response rates. Hematological toxicity, electrolyte disturbance, hemorrhagic cystitis, infectious complications, and hospital admission for fever neutropenia were statistically significant higher for the ICE regimen. Treatment-related mortalities were 2.4% for ICE and 2% for GV (P = 0.86). The 3-year EFS was 39.3% ± 11.4% for ICE and 24.9% ± 12.5% for GV (P = 0.0001), while 3-year OS was 69.3% ± 10.6% and 74% ± 12.9% (P = 0.3), respectively. By multivariate analysis, regimen (P = 0.0001), time to relapse (P = 0.011), B-symptoms (P = 0.001), and leukocytosis (P = 0.007) were significant for EFS, while anemia (P = 0.008), and progressive disease on early response evaluation (P = 0.022) were significant for OS. The ICE regimen had a better overall response rate and EFS, but higher toxicity, than GV; however, OS and mortality were similar.

Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma

AbstractPrevious analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for ≤2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for ≥4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.

KEYFORM-008: Coformulated favezelimab and pembrolizumab (MK4280A) versus chemotherapy in relapsed/refractory classical Hodgkin lymphoma.

TPS7585 Background: PD-1 inhibitors are highly effective in patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but treatment options are limited for pts who have progressed after PD1 blockade. There is an unmet need for effective therapies for anti-PD1 resistant cHL. Upregulation of lymphocyte-activation gene 3 (LAG-3) expression in cHL is proposed to contribute to anti PD-1 resistance (Veldman J et al. Cancer Treat Rev. 2020; 82:101931). The anti–LAG3 antibody favezelimab plus the anti-PD-1 therapy pembrolizumab, has shown promising antitumor activity and manageable safety in pts with R/R cHL after anti-PD1 therapy (Timmerman J et al. Blood 2022; 140). In this ongoing trial, we evaluate the efficacy and safety of MK-4280A in pts with R/R cHL that are refractory to anti-PD1 therapy (ClinicalTrials.gov, NCT05508867). Methods: This randomized, open-label, parallel group, active-controlled phase 3 trial will enroll approximately 360 pts aged ≥ 18 years. Eligible pts will have histologically confirmed R/R cHL, which has progressed on anti-PD-1 mAb and have exhausted all available treatment options with clinical benefit including ineligibility for or failed auto-SCT. In addition, pts must have relapsed after treatment with or failed to respond to brentuximab vedotin (BV), were ineligible for BV or discontinued BV due to toxicity, have ECOG performance status (PS) 0-2, adequate organ function, and availability of archival or newly obtained tissue sample. Pts will be randomized 1:1 to receive MK-4280A (coformulated favezelimab 800 mg/pembrolizumab 200 mg; Arm A) IV Q3W or physician’s choice of gemcitabine (800-1200 mg/m2) IV or bendamustine (90-120 mg/m2) IV (Arm B). Randomization will be stratified by prior auto-SCT (yes vs no), and ECOG PS (0/1 vs 2). Treatment will continue for up to 35 cycles of MK-4280A, or until unacceptable toxicity, disease progression (PD), or withdrawal from trial. Pts in Arm B with PD confirmed by blinded independent central review (BICR) per Lugano criteria may be eligible to crossover to receive up to 35 cycles of MK-4280A. Disease response assessments by PET and CT or MRI will be performed Q12W during the trial. The primary endpoint is progression free survival (PFS) by BICR per Lugano criteria. Secondary endpoints are overall survival (OS), objective response rate (ORR) and duration of response (DOR) (by BICR per Lugano criteria), and safety. Exploratory endpoints include PFS on subsequent oncologic therapy, and pt reported quality of life. Adverse events will be monitored throughout the trial and graded per NCI CTCAE v5.0. PFS, OS and DOR will be estimated using Kaplan-Meier method. ORR with 95% CI will be estimated using the Clopper-Pearson method. Efficacy will be assessed in the intention-to-treat population and safety assessed in all treated pts. Enrollment in this trial is ongoing. Clinical trial information: NCT05508867 .

Combined autologous CD30.CAR‐T cells and nivolumab in patients with relapsed or refractory classical Hodgkin Lymphoma after failure of frontline therapy (ACTION study)

Combined autologous CD30.CAR‐T cells and nivolumab in patients with relapsed or refractory classical Hodgkin Lymphoma after failure of frontline therapy (ACTION study)

Targeted therapy and hematopoietic stem cell transplantation for relapsed/refractory Hodgkin lymphoma in pediatric and adolescent patients: a pilot protocol results

Background. Introduction a targeted drugs in a real clinical practice bring a vast improvement of prognosis in patients with relapsed and refractory (r/r) Hodgkin lymphoma (HL). But it is necessary to increase the experience in anti-CD30 monoclonal antibodies in combination with second-line chemotherapy in pediatric oncology/hematology.&#x0D; Aim. To estimate the effectiveness of chemoimmunotherapy (ViGePD+BV scheme) in pediatric patients with r/r classical HL (cHL).&#x0D; Materials and methods. From January 2018 to October 2022, 15 patients with r/r cHL received scheme ViGePD+BV. Programmed treatment included autologous stem cell transplantation (auto-SCT) in 11 (73%) patients. The potency assignment of antitumour treatment was performed with positron emission tomography/computed tomogtaphy (PET-CT).&#x0D; Results. Complete metabolic response (PET-negative status) was achieved in all 15 (100%) patients after 4 inductive courses by ViGePD+BV scheme; 4-year relapse-free survival was 90.98.7%.&#x0D; Conclusion. Our preliminary data of a pilot protocol of study a chemoimmunotherapy effectiveness for r/r cHL with brentuximab vedotin show a high potency of ViGePD+BV scheme in patients with r/r HL.

Radiation Therapy Use in Refractory and Relapsed Adolescent and Young Adult Hodgkin Lymphoma: A Report from the Children's Oncology Group

Clear indications do not exist for consolidative radiotherapy (CRT) in relapsed and refractory pediatric Hodgkin lymphoma (rrpHL). Increasing numbers of rrpHL patients are radiation naïve, as response-adapted front-line therapies omit CRT for favorable responses. We evaluated practice patterns among treating oncologists for rrpHL. A survey developed by pediatric and radiation oncologists was distributed to Children's Oncology Group (COG) Hodgkin Lymphoma Committee members during the Fall 2021 COG meeting. Questions ascertained respondent specialty and annual rrpHL patient volumes. Respondents provided treatment recommendations for two cases. Case 1: 21-year-old female with stage IIB bulky mediastinal HL treated with ABVDx6 without initial radiotherapy with neck and mediastinal relapse and Deauville 4 (D4) response after 2 second-line chemotherapies. Case 1 was modified (modCase1) to a D2 response after second-line therapy. Case 2: 21-year-old female with non-bulky stage IIB disease treated with ABVDx6 without initial radiotherapy with splenic, mediastinal, and neck relapse and D4 activity in those sites after 2 second-line therapies. Descriptive statistics are presented. 20 (83%) pediatric hematologist/oncologists and 4 (17%) radiation oncologists completed the survey. After autologous stem cell transplant (ASCT) for Case 1, 58% recommended CRT followed by brentuximab vedotin (Bv) maintenance and 33% recommended involved-site radiotherapy (ISRT) alone. For modCase1, 63% would consider CRT instead of ASCT. With ASCT, 21% would recommend CRT to bulk and 38% to all sites at initial relapse. After ASCT for Case 2, 75% recommended ISRT followed by Bv and 17% ISRT alone. In a sample of predominantly pediatric-oncologist COG members, most respondents considered that CRT has a role for patients with radiation-naive rrpHL both for groups with D4 disease as well as D2 disease pre-ASCT.